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Hematopoietic cell transplantation for inherited metabolic diseases: An overview of outcomes and practice guidelines
Abstract
For the past two decades, hematopoietic cell transplantation (HCT) has been used as effective therapy for selected inherited metabolic diseases (IMD) including Hurler (MPS IH) and Maroteaux-Lamy (MPS VI) syndromes, childhood-onset cerebral X-linked adrenoleukodystrophy (X-ALD), globoid-cell leukodystrophy (GLD), metachromatic leukodystrophy (MLD), alpha-mannosidosis, osteopetrosis, and others. Careful pre-HCT evaluation is critical and coordinated, multidisciplinary follow-up is essential in this field of transplantation. The primary goals of HCT for these disorders have been to promote long-term survival with donor-derived engraftment and to optimize the quality of life. Guidelines for HCT and monitoring are provided; a brief overview of long-term results is also presented.
... Hundreds of different IMDs have been identified, most of which are extremely rare. Allogeneic hematopoietic stem cell transplantation (HSCT) is effective in selected types of IMD, especially some types of mucopolysaccharidosis (MPS) and cerebral adrenoleukodystrophy (ALD) [1][2][3][4][5]. Although enzyme replacement therapy (ERT), substrate inhibition, and gene therapy have been developed and an increasing number of patients now benefit from these treatments, HSCT is still preferentially carried out because of its systemic, permanent effects that can be achieved by a single treatment. ...
... However, it was difficult to determine the usefulness of HSCT for other IMDs given the limited experiences of HSCT or inconsistent clinical responses in recipients. After substantial efforts to apply HSCT to various different IMDs, practice guideline showing the tentative indications of HSCT in IMDs was proposed [3]. This guideline was quite informative at the time, but the further accumulation of experience with HSCT for IMDs led to several revisions of the HSCT recommendations over two decades. ...
... The rarity of IMDs made it challenging to establish definitive guidelines for HSCT, and very long-term observation is indispensable, because many IMDs involve problems with the CNS, and changes in bone and other organs (rather than in soft-tissue organs such as the liver or spleen, where clinical improvements can be easily evaluated due to the abundant enzyme supply brought by plentiful blood flow). The consistent consensus indications and the different interpretations of authors as advocated in the successive guidelines are shown in Table 1 [3,[11][12][13]. ...
Allogeneic hematopoietic stem cell transplantation (HSCT) has been used to treat patients with inherited metabolic disorders (IMDs) for more than 40 years. In the first two decades, various IMDs were treated by HSCT with a wide variety of donor sources and conditioning regimens selected at the institutional level. However, HSCT was not always successful due to post-transplant complications such as graft failure. In the third decade, myeloablative conditioning with targeted busulfan-based pharmacokinetic monitoring was established as an optimal conditioning regimen, and unrelated cord blood was recognized as an excellent donor source. During the fourth decade, further improvements were made to transplant procedures, including modification of the conditioning regimen, and the survival rate after HSCT markedly improved. Simultaneously, several long-term observational studies for patients after HSCT clarified its therapeutic effects on growth and development of cognitive function, fine motor skills, and activities of daily living when compared with enzyme replacement therapy. Although immune-mediated cytopenia was newly highlighted as a problematic morbidity after HSCT for IMDs, especially in younger patients who received unrelated cord blood, a recent study with rituximab added to the conditioning raised expectations that this issue can be overcome.
... After uptake, the enzyme is transported to the lysosomes, where it aids in the clearance of stored, undigested material. For example, in the central nervous system (CNS), microglia cells have been shown to be partially replaced by donor cells and transport enzymes to affected neurons (Neuwelt et al. 2008;Krivit et al. 1999;Whitley et al. 1993;Peters and Steward 2003). A second, less important mechanism lies in the ability of the affected patient cells for uptake of functional lysosomal hydrolases released by donor cells to the bloodstream via an endocytosis-mediated mechanism. ...
... However, the remaining disease manifestations particularly orthopedic problems require long-term follow-up and may require surgical intervention. HSCT has also been shown to ameliorate the clinical phenotype in other LSDs including patients with pre-symptomatic or late-onset Krabbe disease (globoid cell leukodystrophy), MPS VI, late-onset forms of MLD, and alpha mannosidosis (Neuwelt et al. 2008;Krivit et al. 1999;Whitley et al. 1993;Peters and Steward 2003). In 1991, the International Society for the Correction of Genetic Diseases by Transplantation (COGENT) established a guideline and proposed that only children under 2.5 years of age with a growth coefficient of 2.5 or smaller than 3 years should be offered an HSCT because of the expected benefits that rapidly decline after this age. ...
... In addition, the risk for the development of an immune response against the proteins delivered through ERT and SRT is considerable and causes a decrease in the effectiveness of these treatments. Since in contrast to the exogenous delivery of enzyme during ERT, in HSCT the enzyme is endogenously produced by the body's own cells, the risks of developing antibodies are much lower (Peters and Steward 2003;de Ru et al. 2011;Hoogerbrugge et al. 1995). ...
Lysosomal storage disorders (LSDs) are rare inborn errors of metabolism caused by defects in lysosomal function. These diseases are characterized by accumulation of completely or partially degraded substrates in the lysosomes leading to cellular dysfunction of the affected cells. Currently, enzyme replacement therapies (ERTs), treatments directed at substrate reduction (SRT), and hematopoietic stem cell (HSC) transplantation are the only treatment options for LSDs, and the effects of these treatments depend strongly on the type of LSD and the time of initiation of treatment. However, some of the LSDs still lack a durable and curative treatment. Therefore, a variety of novel treatments for LSD patients has been developed in the past few years. However, despite significant progress, the efficacy of some of these treatments remains limited because these therapies are often initiated after irreversible organ damage has occurred.Here, we provide an overview of the known effects of LSDs on stem cell function, as well as a synopsis of available stem cell-based cell and gene therapies that have been/are being developed for the treatment of LSDs. We discuss the advantages and disadvantages of use of hematopoietic stem cell (HSC), mesenchymal stem cell (MSC), and induced pluripotent stem cell (iPSC)-related (gene) therapies. An overview of current research data indicates that when stem cell and/or gene therapy applications are used in combination with existing therapies such as ERT, SRT, and chaperone therapies, promising results can be achieved, showing that these treatments may result in alleviation of existing symptoms and/or prevention of progression of the disease. All together, these studies offer some insight in LSD stem cell biology and provide a hopeful perspective for the use of stem cells. Further development and improvement of these stem cell (gene) combination therapies may greatly improve the current treatment options and outcomes of patients with a LSD.
... Over the past 20 years, hematopoietic stem cell transplantation (HSCT) has been the only clinically available therapeutic option for juvenile MLD [5]. The rationale is that monocytic bone marrow cells can cross the bloodbrain barrier, migrate into the brain, differentiate into microglia cells and produce the missing enzyme, thereby enabling re-myelination [6,7]. ...
... The rationale is that monocytic bone marrow cells can cross the bloodbrain barrier, migrate into the brain, differentiate into microglia cells and produce the missing enzyme, thereby enabling re-myelination [6,7]. It takes up to 12-24 months until disease stabilization occurs because of the slow replacement of resident tissue [5,[8][9][10], which in turn makes HSCT ineffective in children with the rapidly progressive late-infantile form and in juvenile patients with advanced symptoms [11]. The main reason for a good outcome in children with the juvenile form is considered to be the early clinical disease stage at transplantation, with sufficient time until severe disease progression. ...
... The main reason for a good outcome in children with the juvenile form is considered to be the early clinical disease stage at transplantation, with sufficient time until severe disease progression. Patients who underwent transplantation at an early disease stage, with low motor and neurocognitive impairment, or at a pre-symptomatic stage, exhibited a better long-term outcome than patients in advanced stages of the disease [5,6,[12][13][14][15][16][17][18]. Nevertheless, due to variable outcomes [8][9][10][19][20][21][22] and the frequent lack of comparisons between the outcomes in transplanted and non-transplanted patients, whether HSCT is an option for treatment of MLD remains controversial [5,6,13,23]. ...
Background:
Long-term outcomes of hematopoietic stem cell transplantation (HSCT) in children with juvenile metachromatic leukodystrophy (MLD) have been investigated systematically, while short-term effects of HSCT on the course of the disease remain to be elucidated.
Results:
In this study, the clinical course was evaluated over the first 24 months following HSCT, conducted at our center in 12 children with juvenile MLD (mean follow-up 6.75 years, range 3-13.5) and compared with 35 non-transplanted children with juvenile MLD. Motor function (GMFM-88 and GMFC-MLD), cognitive function (FSIQ), peripheral neuropathy (tibial nerve conduction velocity), and cerebral changes (MLD-MR severity score) were tested prospectively. Seven children remained neurologically stable over a long period, five exhibited rapid disease progression over the first 12 to 18 months after transplantation. In the latter, time from first gross motor symptoms to loss of independent walking was significantly shorter compared with non-transplanted patients at the same stage of disease (p < 0.02). Positive prognostic factors were good motor function (GMFM = 100%, GMFC-MLD = 0) and a low MR severity score (≤ 17) at the time of HSCT.
Conclusions:
Our results show that if disease progression occurs, this happens early on after HSCT and proceeds faster than in non-transplanted children with juvenile MLD, indicating that HSCT may trigger disease progression.
... Because the biochemical improvement and the reversal of the clinical features of the Hurler syndrome (Hobbs et al, 1981), hematopoietic cell transplantation (HCT) from allogeneic healthy donors has been adopted for the treatment of several LSDs (Peters & Steward, 2003;Staba et al, 2004;Escolar et al, 2005). The transplanted hematopoietic cells and/or their progenies can provide a stable source of non-defective enzyme in the affected tissues. ...
... However, the efficacy of HCT has only been proven in a few selected LSDs so far (Walker & Montell, 2016). Moreover, very few studies have reported a successful improvement of neurological symptoms by HCT (Peters & Steward, 2003). On the other hand, autologous hematopoietic stem cell transplantation (aHSCT) is currently considered as a highly effective treatment for severe autoimmune diseases such as multiple sclerosis (MS) (Giedraitiene et al, 2022;Nabizadeh et al, 2022;Ruder et al, 2022;Willison et al, 2022). ...
Niemann–Pick disease type C1 (NPC1) is a fatal lysosomal storage disorder characterized by progressive neuronal degeneration. Its key pathogenic events remain largely unknown. We have, herein, found that neonatal BM–derived cell transplantation can ameliorate Purkinje cell degeneration in NPC1 mice. We subsequently addressed the impact of the peripheral immune system on the neuropathogenesis observed in NPC1 mice. The depletion of mature lymphocytes promoted NPC1 phenotypes, thereby suggesting a neuroprotective effect of lymphocytes. Moreover, the peripheral infusion of CD4-positive cells (specifically, of regulatory T cells) from normal healthy donor ameliorated the cerebellar ataxic phenotype and enhanced the survival of Purkinje cells. Conversely, the depletion of regulatory T cells enhanced the onset of the neurological phenotype. On the other hand, circulating inflammatory monocytes were found to be involved in the progression of Purkinje cell degeneration, whereas the depletion of resident microglia had little effect. Our findings reveal a novel role of the adaptive and the innate immune systems in NPC1 neuropathology.
... In the past, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been the only clinically available treatment [9]. Nowadays, new therapeutic options are upcoming. ...
... It has to be noted that the early course after allo-HSCT determines the long-term outcome. Clinical disease progression occurs in the first 12-18 months after transplantation and neurological progression becomes less likely if patients remain stable throughout this period [2,9,21,[24][25][26]. Risk factors for clinical deterioration following allo-HSCT involve inflammatory responses induced by this procedure [2,15]. ...
Metachromatic leukodystrophy (MLD) is a neurodegenerative lysosomal storage disorder caused by biallelic pathogenic variants in the gene encoding arylsulfatase A. Disease onset is variable (with late infantile, early and late juvenile, and adult forms) and treatment options depend on age and disease symptoms at onset. In the past, allo-hematopoietic stem cell transplantation (allo-HSCT) has been the best treatment option, following strict selection criteria. The outcome however is variable and morbidity remains high. This paved the way to the development of new treatment options, some of them aiming to be curative. In the light of this changing therapeutic field, newborn screening is becoming a valuable option. This narrative review aims to describe the outcome of allo-HSCT in the different MLD disease forms, and, in addition, reviews new treatment options. Finally, the shift of the field towards newborn screening for MLD is discussed.
... The first successful BMT was performed in a Hurler syndrome patient (37) and it is now the standard treatment procedure used for infants with Hurler syndrome showing no positive response to ERT to prevent the development of neurological symptoms (38). Also, few studies prove that BMT prevented the onset of both (39,40). The biggest challenge is that the success of transplantation varies between organ systems with rapid improvement in hematological and physical characters. ...
... The biggest challenge is that the success of transplantation varies between organ systems with rapid improvement in hematological and physical characters. Several authors have observed regression in the liver, spleen, and skeletal changes (39,41). In the case of Gaucher disease, the available evidence on the beneficial effect of BMT on neurological manifestation for type 2 and type 3 patients is unfavorable due to variable response (42)(43)(44). ...
Lysosomal storage disorders comprise a group of approximately 70 types of inherited diseases resulting due to lysosomal gene defects. The outcome of the defect is a deficiency in either of the three: namely lysosomal enzymes, activator protein, or transmembrane protein as a result of which there is an unwanted accumulation of biomolecules inside the lysosomes. The pathophysiology of these conditions is complex affecting several organ systems and nervous system involvement in a majority of cases. Several research studies have well elucidated the mechanism underlying the disease condition leading to the development in devising the treatment strategies for the same. Currently, these approaches aim to reduce the severity of symptoms or delay the disease progression but do not provide a complete cure. The main treatment methods include Enzyme replacement therapy, Bone marrow transplantation, Substrate reduction therapy, use of molecular chaperones, and Gene therapy. This review article presents an elaborate description of these strategies and discusses the ongoing studies for the same.
... QOL has been described as a fundamental component of phenotype in genetic disorders generally, 27 and specifically in lysosomal disorders and leukodystrophies, the class of disorders that includes KD. [28][29][30] Proprietary QOL questionnaires have been applied to various pediatric illnesses, for example, sickle cell disease, 31 ...
... It may consequently find use in future research that examines benefits of therapies for neurodegenerative disorders, in which QOL is indeed recognized as an important outcome of treatment. [28][29][30] It is possible that the survey could be shortened to include the items contributing most to the KD phenotypic difference (Table 4). However, determination of its final iteration will require testing more broadly in KD and other neurodegenerative illnesses. ...
Objectives
To develop a quality of life (QOL) survey for Krabbe disease (KD), and to thereby improve understanding of its phenotypic expression and response to treatment.
Methods
The survey, the Leukodystrophy Quality of Life Assessment (LQLA) and the Vineland Adaptive Behavior Scales were co‐administered to 33 patients or their caretakers. These included the phenotypes of early infantile KD (EIKD; 0‐6 months old at onset), late infantile cases (LIKD; 7‐12 months old at onset), and cases that emerged after 12 months old, late onset (LOKD). The sample included cases with and without stem cell transplantation (SCT). Reliability and concurrent validity were assessed for overall and subscale scores. Analysis of variance tested differences in QOL between phenotypes and transplant groups (none, pre‐, post‐symptom).
Results
Good concurrent validity with the Vineland was shown for total, communication, daily activity, social, and motor scales and good reliability was observed. LOKD cases had better communication skills than either EIKD or LIKD and better overall QOL than EIKD. Analyses of individual items showed that communication items, mostly, contributed significantly to phenotype differences. Presymptomatic SCT significantly improved QOL compared to postsymptomatic SCT or no treatment. Presymptomatically treated patients had near‐normal total scores.
Conclusions
The LQLA is valid and reliable. Despite small sample size, phenotypic demarcation was determined to be due mainly to differences in communication skills. There was a relative enhancement of QOL in LOKD patients, and in those who had presymptomatic SCT. These results apply to the current controversy about recommendations for newborn screening for this condition.
... Moreover, because of the low prevalence, most pediatricians are poorly aware of it, also leading to delays in diagnosis. Although hematopoietic stem cell transplantation and enzyme replacement therapy are effective treatment methods for MPS, the early time of therapy greatly in uences the prognosis [7][8][9][10] . ...
Background
To explore the significance of Mongolian spots for the primary screening of mucopolysaccharidosis (MPS).
Method
In this study, the incidence, size, number, distribution, and regression of Mongolian spots in 225 patients diagnosed with MPS in China followed between 2020 and 2021 were retrospectively investigated, and compared with those in 209 normal newborns.
Results
The diagnostic age ranged from 0 to 32 years old with a median diagnostic age was 3 years old. Although the total incidence of MPS patients with Mongolian spots (73.78%) was higher than that in normal newborns (66.51%), there was no statistical significance. The incidence of Mongolian spots ≥ 2 or ≥ 5 in MPS group was significantly higher than that in control group (P < 0.001). The average number of Mongolian spots in MPS patients at least greater than or equal to (2.84 ± 2.47) was higher than that in normal newborns (1.09 ± 1.33) with a significant difference (P < 0.001). The age of diagnosis with less than 2 Mongolian spots (median diagnostic age = 4.00) was later than with greater than or equal to 2 Mongolian spots (median diagnostic age = 3.00) in MPS group (z=-3.103, P = 0.002). The age of diagnosis with less than 5 Mongolian spots (median diagnostic age = 4) was later than with greater than or equal to 5 Mongolian spots (median diagnostic age = 3) in MPS group (z=-2.728, P = 0.006). Comparing MPS groups (median maximum length = 7.0cm) and control groups (median maximum length = 3.0cm), the two groups were statistically different (z=-7.801, P < 0.001). In MPS group, Mongolian spots were mainly distributed in the buttocks (81.93%) and back (68.07%), followed by the lower limbs (27.71%), abdomen (22.29%), and upper limbs (19.88%), with fewer distribution in areas such as the head, face, neck, and chest. Among the MPS patients born with Mongolian spots, there were 19.28% of patients had the disappearance of Mongolian spots by the time of investigation.
Conclusions
This study demonstrated Mongolian spots were a common feature in patients with MPS, especially in type 2, 1, and 6. Extensive Mongolian spots might be an indicator for early screening of MPS.
... High protein intake may aggravate UCDs. Bone marrow transplantation may be helpful in MLD, Krabbe disease, and some mucopolysaccharidoses [71]. It works well in MLD in early stages (preferably before symptoms appear) but can work even late in Krabbe disease, even reversing some symptoms. ...
There is no dearth of literature detailing individual inborn neurometabolic disorders (INMDs), but it is hard to find a systematic approach to precisely diagnose these. Early diagnosis can go a long way in managing them and improving quality of life and cure in some cases. A systematic structured approach taking into account age, type of presentation, clinical features, imaging, biochemical tests, histopathology and molecular diagnostics often helps in arriving at a particular diagnosis, or a broad category of disorders, which helps in further management. Newer treatment options such as bone marrow transplantation, umbilical cord blood stem cell transplantation, enzyme substitution, somatic gene therapy, and fetal neuronal transplants have given a ray of hope, making it imperative to arrive at early diagnosis of these conditions. Even if a child is lost to inborn error of metabolism (IEM), the cord blood of a normal sibling may be frozen as a reservoir for stem cells for an affected sibling in future pregnancies. In this chapter, we would try to evolve a systematic approach for diagnosis of IEMs and to narrow down the list of differentials. This will lead to cost-effective yet precise biochemical, genetic, and molecular tests to arrive at a final diagnosis.
... These results indicate that MAF increases cell permeability but does not induce a prothrombotic phenotype on the endothelium. Allo-HCT remains the most extended immunotherapy for various hematological and non-hematological diseases [33,34]. Some changes in allo-HCT process provoked a better response in the last years, mainly, considering the adjustment of treatment intensity in conditioning regimen and the T lymphocyte attenuation of the graft and patient. ...
Post-transplantation cyclophosphamide (PTCy) has decreased GVHD incidence. Endothelial damage in allo-HCT is caused by multiple factors, including conditioning treatments and some immunosupressants, and underlies HCT-complications as GVHD. Nevertheless, the specific impact of PTCy on the endothelium remains unclear. We evaluated the effect of mafosfamide (MAF), an active Cy analog, on endothelial cells (ECs) vs. cyclosporine A (CSA), with known damaging endothelial effect. ECs were exposed to MAF and CSA to explore changes in endothelial damage markers: (i) surface VCAM-1, (ii) leukocyte adhesion on ECs, (iii) VE-cadherin expression, (iv) production of VWF, and (v) activation of intracellular signaling proteins (p38MAPK, Akt). Results obtained (expressed in folds vs. controls) indicate that both compounds increased VCAM-1 expression (3.1 ± 0.3 and 2.8 ± 0.6, respectively, p < 0.01), with higher leukocyte adhesion (5.5 ± 0.6, p < 0.05, and 2.8 ± 0.4, respectively). VE-cadherin decreased with MAF (0.8 ± 0.1, p < 0.01), whereas no effect was observed with CSA. Production of VWF augmented with CSA (1.4 ± 0.1, p < 0.01), but diminished with MAF (0.9 ± 0.1, p < 0.05). p38MAPK activation occurred with both compounds, being more intense and faster with CSA. Both drugs activated Akt, with superior MAF effect at longer exposure. Therefore, the cyclophosphamide analog MAF is not exempt from a proinflammatory effect on the endothelium, though without modifying the subendothelial characteristics.
... 62 Also, different aspects of the transplant like donor enzyme level, degree, and persistence of donor chimerism, and post-transplant complications influence the outcomes of BMT and its success. 63 Literature has shown considerable data on the success of HSCT in MPS I patients. European data has also shown improvement in event-free transplant survival from 58% (1994-2004 data) to 91% (2005-2008 data) for MPS I patients. ...
Lysosomal storage disorders (LSDs) are a group of seventy different metabolic storage diseases due to accumulation of substrate mainly in the form of carbohydrate, lipids, proteins, and cellular debris. They occur due to variant in different genes that regulate lysosomal enzymes synthesis, transport, and secretion. In recent years, due to an increased availability of various therapies to treat these disorders, and increased diagnostic tools, there has been an escalated awareness of LSDs. Due to heterogeneous population and various social reasons, India is likely to have a high frequency of LSDs. Therefore, to understand the burden of various LSDs, its molecular spectrum, and understanding the phenotype–genotype correlation, Indian Council of Medical Research (ICMR) and Department of Health Research (DHR), Government of India had set up a task force in the year 2015. It has resulted in identifying common LSDs, and founder variant for some of the storage disorders and molecular spectrum of various LSDs across the country. This review describes in detail the spectrum of LSDs, its molecular epidemiology and prevention in context to Indian population.
... Allo-HCT remains the most extended immunotherapy for various hematological and non-hematological diseases (30,31). Some changes in allo-HCT process provoked a better response in the last years, mainly, considering the adjustment of treatment intensity in conditioning regimen and the T lymphocyte attenuation of the graft and patient. ...
Post-transplantation cyclophosphamide (PTCy) has decreased GVHD incidence. Endothelial damage in allo-HCT is caused by multiple factors, including conditioning treatments and some immunosupressants, and underlies HCT-complications as GVHD. Nevertheless, the specific impact of PTCy on the endothelium remains unclear. We evaluated the effect of mafosfamide (MAF), an active Cy analog, on endothelial cells (ECs) vs. cyclosporine A (CSA), with known damaging endothelial effect. ECs were exposed to MAF and CSA to explore changes in endothelial damage markers: i) surface VCAM-1, ii) leukocyte adhesion on ECs, iii) VE-cadherin expression, iv) production of VWF, and v) activation of intracellular signaling proteins (p38MAPK, Akt). Results obtained (expressed in folds vs. controls) indicate that both compounds increased VCAM-1 expression (3.1 ± 0.3 and 2.8 ± 0.6, respectively, p < 0.01), with higher leukocyte adhesion (5.5 ± 0.6, p < 0.05, and 2.8 ± 0.4, respectively). VE-cadherin decreased with MAF (0.8 ± 0.1, p < 0.01), whereas no effect was observed with CSA. Production of VWF augmented with CSA (1.4 ± 0.1, p < 0.05), but diminished with MAF (0.9 ± 0.1, p < 0.05). p38MAPK activation occurred with both compounds, being more intense and faster with CSA. Both drugs activated Akt, with superior MAF effect at longer exposure. Therefore, the cyclophosphamide analog MAF is not exempt from a proinflammatory effect on the endothelium, though without modifying the subendothelial characteristics.
... As the European Group for Blood and Marrow Transplantation Guidelines suggests, in individuals with MLD, HSCT is "recommended in presymptomatic individuals or while neuropsychologic function and independence in activities of daily living remain good. " [19]. This urgency to treat is exemplified by the short window of opportunity before rapid and devastating disease progression occurs. ...
Background
Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy, Libmeldy (atidarsagene autotemcel), was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes insights into the caregiver language used to describe initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis.
Results
Data was collected through a moderator-assisted online 60-min survey and 30-min semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n = 10), France (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 20), juvenile (n = 11) or borderline late infantile/juvenile (n = 1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child’s initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms of MLD and provide added context to help elevate the index of suspicion of disease. Distinctions between caregiver descriptions of late infantile and juvenile MLD in symptom onset and disease course were also identified.
Conclusions
This study captures the caregiver description of the physical, behavioral, and cognitive signs of MLD prior to diagnosis. The understanding of the caregiver language at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.
... BMT is also widely used in other LSD disorders such as globoid cell leukodystrophy. 120,121 Glycolipid storage diseases are inherited disorders in which enzymes for the degradation of glycosphingolipids are missing, which eventually leads to CNS degeneration. 122 Sandhoff disease is a glycolipid storage disease characterized by a lack of lysosomal β-hexosaminidase and the subsequent accumulation of β-hexosaminidase in the CNS. ...
Circulating monocytes are precursors of both tissue macrophages and dendritic cells, and they can infiltrate the central nervous system (CNS) where they transform into bone marrow‐derived macrophages (BMDMs). BMDMs play essential roles in various CNS diseases, thus modulating BMDMs might be a way to treat these disorders because there are currently no efficient therapeutic methods available for most of these neurological diseases. Moreover, BMDMs can serve as promising gene delivery vehicles following bone marrow transplantation for otherwise incurable genetic CNS diseases. Understanding the distinct roles that BMDMs play in CNS diseases and their potential as gene delivery vehicles may provide new insights and opportunities for using BMDMs as therapeutic targets or delivery vehicles. This review attempts to comprehensively summarize the neurological diseases that might be treated by modulating BMDMs or by delivering gene therapies via BMDMs after bone marrow transplantation.
... Hematopoietic stem cell transplantation (HSCT) is another option for MPS II treatment and is expected to have a similar long-term effect to ERT in visceral diseases [5]. Although HSCT ameliorates CNS involvement in several lysosomal storage diseases (LSD), such as MPS I-Hurler syndrome [6], its impact on CNS in MPS II patients is still unclear [7][8][9][10][11]. ...
A hematopoietic stem cell (HSC) gene therapy (GT) using lentiviral vectors has attracted interest as a promising treatment approach for neuropathic lysosomal storage diseases. To proceed with the clinical development of HSC-GT, evaluation of the therapeutic potential of gene-transduced human CD34+ (hCD34+) cells in vivo is one of the key issues before human trials. Here, we established an immunodeficient murine model of mucopolysaccharidosis type II (MPS II), which are transplantable human cells, and demonstrated the application of those mice in evaluating the therapeutic efficacy of gene-modified hCD34+ cells. NOG/MPS II mice, which were generated using CRISPR/Cas9, exhibited a reduction of disease-causing enzyme iduronate-2-sulfatatase (IDS) activity and the accumulation of glycosaminoglycans in their tissues. When we transplanted hCD34+ cells transduced with a lentiviral vector carrying the IDS gene into NOG/MPS II mice, a significant amelioration of biochemical pathophenotypes was observed in the visceral and neuronal tissues of those mice. In addition, grafted cells in the NOG/MPS II mice showed the oligoclonal integration pattern of the vector, but no obvious clonal dominance was detected in the mice. Our findings indicate the promising application of NOG/MPS II mice to preclinical study of HSC-GT for MPS II using human cells.
... As the European Group for Blood and Marrow Transplantation Guidelines suggests, in individuals with MLD, HSCT is "recommended in presymptomatic individuals or while neuropsychologic function and independence in activities of daily living remain good." [15]. This urgency to treat is exempli ed by the short window of opportunity before rapid and devastating disease progression occurs. ...
Background: Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes a caregiver perspective of initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis.
Results: Data was collected through a moderator-assisted online 60-minute survey and 30-minute semi-structured follow-up telephone interview with 31 MLD caregivers in the United States (n=10), France (n=10), the United Kingdom (n=5), and Germany (n=6). All respondents were primary caregivers of a person with late infantile (n=20), juvenile (n=11) or borderline late infantile/juvenile (n=1) MLD (one caregiver reported for 2 children leading to a sample of 32 individuals with MLD). Caregivers were asked questions related to their child’s initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms, which can be summarized as coordination difficulties, clonus/tremors, and comprehension challenges in the absence of notable prior history. Distinctions between late infantile versus juvenile MLD in symptom onset and disease course were also identified.
Conclusions: This study captures the caregiver language on the physical, behavioral, and cognitive signs of MLD leading up to diagnosis. The understanding of the caregiver experience at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.
... Initial studies reported a high incidence of transplantation failure (15-75%), as well as elevated mortality related to the lack of availability of unrelated donors and rapid disease progression (Escolar et al., 2005;Peters et al., 2003;Boelens, 2006). Nonetheless, identifying graft rejection risk factors as well as improving HSCT techniques, including rapid availability of umbilical cords, has resulted in less graft rejection and less mortality after transplantation. ...
Mucopolysaccharidoses (MPSs) are a heterogeneous group of diseases that have in common the accumulation of glycosaminoglycans (mucopolysaccharides) within the lysosome. The diseases are caused by a deficiency of the enzyme α-L-iduronidase which is responsible for the degradation of glycosaminoglycans (GAGs or mucopolysaccharides). More than 100 mutations in the gene have been reported, resulting in marked clinical/response variability. MPSs usually present as multisystem and progressive clinical disorders which affect psychomotor and cardiovascular development, the cornea and the musculoskeletal system. Seven phenotypically distinct diseases have been described, and MPS type I (MPS-I) is divided into three clinical forms: severe (Hurler syndrome), intermediate (Hurler-Scheie syndrome) or mild (Scheie syndrome).
For the treatment of MPS-I, Enzyme Replacement Therapy (ERT) with α-L-iduronidase and Hematopoietic Stem Cells Transplantation (HSCT), separately or in combination, have produced clinical improvement, especially with regards cardiovascular symptoms and psychomotor development. This article presents the long-term (seven years) follow-up of monochorionic, diamniotic twins who were diagnosed with MPS-I at an early stage, and treated with ERT (from age 10 months) plus HSCT (from age 18 months). Overall, the treatment has facilitated stable development with an overall good response and better control of symptoms associated with MPS-I.
... As the European Group for Blood and Marrow Transplantation Guidelines suggests, in patients with MLD, HSCT is "recommended in presymptomatic patients or while neuropsychologic function and independence in activities of daily living remain good." [13]. This urgency to treat is exempli ed by the limited window before rapid and devastating disease progression occurs. ...
Background
Metachromatic leukodystrophy (MLD), a relentlessly progressive and ultimately fatal condition, is a rare autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme arylsulfatase A (ARSA). Historically management has been palliative or supportive care. Hematopoietic stem cell transplantation is poorly effective in early-onset MLD and benefit in late-onset MLD remains controversial. Hematopoietic stem cell gene therapy was recently approved by the European Medicines Agency for early-onset MLD. Treatment benefit is mainly observed at an early disease stage, indicating the need for early diagnosis and intervention. This study contributes a caregiver perspective of initial MLD symptomatology, and thereby aims to improve communication between clinicians and families impacted by this condition and promote a faster path to diagnosis.
Results
Data was collected through a moderator-assisted online 60-minute survey and 30-minute semi-structured follow-up telephone interview with 21 MLD caregivers in the United States (n = 10), the United Kingdom (n = 5), and Germany (n = 6). All respondents were primary caregivers of a person with late infantile (n = 13), juvenile (n = 7) or borderline late infantile/juvenile (n = 1) MLD. Caregivers were asked questions related to their child’s initial signs and symptoms, time to diagnosis and interactions with healthcare providers. These results highlight the caregiver language used to describe the most common initial symptoms, which can be summarized as developmental stagnation, difficulty walking/running, and clonus/tremors, in the absence of notable prior history. Distinctions between late infantile versus juvenile MLD in symptom onset and disease course were also identified.
Conclusions
This study captures the most frequent caregiver-reported physical, behavioral, and cognitive signs of MLD leading up to diagnosis. The understanding of the caregiver experience at symptom onset sheds light on a critical window of often missed opportunity for earlier diagnosis and therapeutic intervention in MLD.
... Several reports have shown that various late-onset leukodystrophies, such as X-linked adrenoleukodystrophy (ALD) and Krabbe disease (KD), may present as spastic paraplegia (SP) without leukodystrophy on neuroimaging and be easily misdiagnosed as hereditary spastic paraplegia (HSP) on clinical grounds. [2][3][4][5] Currently, no effective treatment is available for HSP, but recent breakthroughs in the treatment of leukodystrophy, such as enzyme replacement therapy and hematopoietic stem cell transplantation, [6][7][8] have provided more opportunities for improving the clinical outcome of patients with leukodystrophy. Therefore, the early differentiation of leukodystrophy from HSP is of great importance in improving patients' prognosis and in providing early treatment opportunities for other pedigree members. ...
Purpose:
Leukodystrophies are frequently regarded as childhood disorders, but they can occur at any age, and the clinical and imaging patterns of the adult-onset form are usually different from the better-known childhood variants. Several reports have shown that various late-onset leukodystrophies, such as X-linked adrenoleukodystrophy and Krabbe disease, may present as spastic paraplegia with the absence of the characteristic white matter lesions on neuroimaging; this can be easily misdiagnosed as hereditary spastic paraplegia. The objective of this study was to investigate the frequency of late-onset leukodystrophies in patients with spastic paraplegia.
Patients and methods:
We performed genetic analysis using a custom-designed gene panel for leukodystrophies in 112 hereditary spastic paraplegia-like patients.
Results:
We identified pathogenic mutations in 13 out of 112 patients, including five patients with adrenomyeloneuropathy, three with Krabbe disease, three with Alexander disease, and two with cerebrotendinous xanthomatosis. In terms of clinical manifestations, in addition to spastic paraplegia, three adrenomyeloneuropathy probands also had adrenocortical insufficiency, two Alexander disease probands developed urinary retention, one CTX proband developed cataracts and chronic diarrhea and the other presented with chronic diarrhea and mild tendon xanthomatosis. None of the patients had evidence of diffuse leukodystrophy on neuroimaging.
Conclusion:
Patients with late-onset spastic paraplegia should be screened for underlying leukodystrophies, irrespective of the presence of additional complicating symptoms and neuroimaging abnormalities.
... Generally, disease stabilization is expected within 6 to 24 months after HSCT. 16,19,20 On brain MRI, patient B progressed from MRI-MLD score 11 5 to 13/34 in the posttransplantation period. MRI-MLD score had improved again (11/34) already 5 months later (Figure 2). ...
Two siblings were diagnosed with adult metachromatic leukodystrophy (MLD) and treated with hematopoietic stem cell transplantation (HSCT). While the older sibling was symptomatic at the time of diagnosis, her younger brother was diagnosed and transplanted at the presymptomatic state. We describe patients' clinical, biochemical, and genetic features, as well as neuropsychological and neurophysiological test results, and brain magnetic resonance imaging from pretransplantation and posttransplantation assessments. Both patients converted to complete donor chimerism and arylsulfatase A levels normalized 3 months posttransplantation. Twelve months posttransplantation, neurological and neuropsychological assessment for both patients showed stabilization, and they remained stable for the 38 months long observation period. To assess the effect of HSCT used as treatment for the rare, adult MLD subtype on survival and stabilization, we performed a systematic literature review and included 7 studies with a total of 26 cases. Of these 26 cases, 6 patients died of HSCT‐related complications and 2 patients had graft rejection. Of the remaining 18 patients, 2 patients improved after HSCT, 13 patients stabilized, and 3 patients progressed, suggesting that HSCT potentially benefits adult MLD patients. Larger studies focusing on this subtype are needed and recommendations on criteria for HSCT in adult MLD need to be evolved.
... ARSA deficient MLD patients consequently lack sufficient sphingolipids, thus leading to downstream myelin deficits (Biffi et al., 2006). Original MLD therapies included hematopoietic cell or bone marrow transplantations (BMT) but were limited in their therapeutic success (Krivit et al., 1999;Peters and Steward, 2003). Since then, use of lentiviruses and AAVs have proven more promising; LV treatment of microglial populations in the tremor mouse model has exhibited restorative functions (Biffi et al., 2006) and AAVrh10 carrying the ARSA transgene has been found to correct for MLD by targeting up to 21% of oligodendrocytes (Piguet et al., 2012). ...
In recent years, the scientific and therapeutic fields for rare, genetic central nervous system (CNS) diseases such as leukodystrophies, or white matter disorders, have expanded significantly in part due to technological advancements in cellular and clinical screenings as well as remedial therapies using novel techniques such as gene therapy. However, treatments aimed at normalizing the pathological changes associated with leukodystrophies have especially been complicated due to the innate and variable effects of glial abnormalities, which can cause large-scale functional deficits in developmental myelination and thus lead to downstream neuronal impairment. Emerging research in the past two decades have depicted glial cells, particularly oligodendrocytes and astrocytes, as key, regulatory modulators in constructing and maintaining myelin function and neuronal viability. Given the significance of myelin formation in the developing brain, myelin repair in a time-dependent fashion is critical in restoring homeostatic functionality to the CNS of patients diagnosed with white matter disorders. Using Canavan Disease (CD) as a leukodystrophy model, here we review the hypothetical roles of N-acetylaspartate (NAA), one of the brain's most abundant amino acid derivatives, in Canavan disease's CNS myelinating pathology, as well as discuss the possible functions astrocytes serve in both CD and other leukodystrophies' time-sensitive disease correction. Through this analysis, we also highlight the potential remyelinating benefits of gene therapy for other leukodystrophies in which alternative CNS cell targeting for white matter disorders may be an applicable path for reparative treatment.
... However, a significant residual disease burden remained, and as lifespan was increased, various clinical manifestations emerged during long-term follow-up. In general, the outcomes of HSCT are affected by various aspects of the transplant such as haploidentity between the donor and recipient, severity of myeloablative conditioning, phenotypic severity at the age of HSCT, degree and persistence of donor chimerism and post-transplant complications [71,72]. A critical predictor for better outcome is sufficient circulating enzyme concentrations obtained post-HSCT, which could be affected by the degree of donor chimerism. ...
Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years.
... Allogeneic HSCT is considered the gold standard for treatment of Hurler syndrome and can alleviate a number of disease symptoms and increase the patient's life span, especially when performed before the age of 2 years and prior to cognitive impairment [4][5][6][7][8]. Clinical effect is evident in reduced facial coarseness, joint mobility, and reduction in sleep apnea, cardiac disease, and hearing loss [9][10][11]. Overall, survival is significantly prolonged [4,12,13], and when initiated early, decline of neurocognition can be stabilized [8]. ...
Mucopolysaccharidosis type I (MPS I) is a lysosomal disease, caused by a deficiency of the enzyme alpha-L-iduronidase (IDUA). IDUA catalyzes the degradation of the glycosaminoglycans dermatan and heparan sulfate (DS and HS, respectively). Lack of the enzyme leads to pathologic accumulation of undegraded HS and DS with subsequent disease manifestations in multiple organs. The disease can be divided into severe (Hurler syndrome) and attenuated (Hurler-Scheie, Scheie) forms. Currently approved treatments consist of enzyme replacement therapy (ERT) and/or hematopoietic stem cell transplantation (HSCT). Patients with attenuated disease are often treated with ERT alone, while the recommended therapy for patients with Hurler syndrome consists of HSCT. While these treatments significantly improve disease manifestations and prolong life, a considerable burden of disease remains. Notably, treatment can partially prevent, but not significantly improve, clinical manifestations, necessitating early diagnosis of disease and commencement of treatment. This review discusses these standard therapies and their impact on common disease manifestations in patients with MPS I. Where relevant, results of animal models of MPS I will be included. Finally, we highlight alternative and emerging treatments for the most common disease manifestations.
... The alternative treatment for GD, Eliglustat, a substrate reduction therapy (SRT), was only indicated for adult patients with GD type 1. Miglustat, another SRT, may have positive results on pulmonary function but failed to show improvement in neurological manifestations [16]. Allogeneic hematopoietic stem cell transplantation(HSCT), the only curative treatment for GD, is effective in alleviating most GD manifestations: improvements in hematological profile, regressing the size of reticuloendothelial organs, reducing skeletal problems, and even arresting neuropsychological deterioration in some [17,18]. Nevertheless, HSCT is less considered as a treatment option for GD type 1 and even GD type 3 because of the substantial risk and the general success of ERT and SRT for controlling the common clinical manifestations of GD. ...
Objective
To provide strategies for monitoring and treating severe lung involvement in Gaucher disease.
Study design
We reviewed the chart of a 5-year-old boy who developed rapidly progressive, severe infiltrative lung involvement of Gaucher disease (GD) and improved after allogeneic hematopoietic stem cell transplant (HSCT), along with other case studies reported before December 2019. He was diagnosed with GD (homozygous mutation at c.1448 T > C, p.L483P), and started receiving enzyme replacement therapy (ERT) at 17 months old. He developed respiratory distress symptoms after 45 months of ERT; chest imaging reported diffuse interstitial infiltration of the bilateral lungs and consolidations at the right lungs. Allogeneic HSCT using cells from a matched unrelated donor was performed four months upon progressive respiratory symptoms.
Results
His respiratory symptoms subsided in one month; chest imaging improvement, pulmonary function test improvement, and normalized activity of β-glucocerebrosidase were reported in three months.
Conclusion
This is the first report of a patient who received early and regular ERT but developed severe infiltrative lung involvement and recovered after allogeneic HSCT. Based on study results, we suggest regular chest imaging, even for asymptomatic patients. For patients with severe lung involvement, rapid deterioration, and unresponsive to higher ERT dosages, allogeneic HSCT should be considered.
... These data seem highly relevant, not only for improved counseling of patients with MLD and their families but also, and especially, with respect to therapeutic approaches, whether these involve hematopoietic stem cell transplantation, enzyme replacement, or gene therapy. 9,[19][20][21] For all these approaches, an effect is reported primarily when implemented as early as possible during the disease course or even at a presymptomatic stage. On the basis of the data presented here, which indicate that the course of disease in patients with later onset is predicted by the type of first symptoms, individually tailored therapeutic decisions could be improved, depending on whether a more rapid or a more protracted course is to be expected. ...
Objective:
To compare disease progression between different onset forms of Metachromatic Leukodystrophy (MLD) and to investigate the influence of the type of first symptoms on the natural course and dynamic of disease progression.
Methods:
Clinical, genetic and biochemical parameters were analyzed within a nationwide study of patients with late-infantile (LI, onset ≤ 2.5 years), early-juvenile (EJ, onset 2.6 - < 6 years), late-juvenile (LJ, onset 6 - < 16 years), and adult (onset ≥ 16 years) forms of MLD. First symptoms were categorized as motor symptoms only, cognitive symptoms only, or both.. Standardized clinical endpoints included loss of motor and language functions, as well as dysphagia/tube feeding.
Results:
97 Patients with MLD were enrolled. Patients with LI (n=35) and EJ (n=18) MLD exhibited similarly rapid disease progression, all starting with motor symptoms (with or without additional cognitive symptoms). In LJ (n=38) and adult-onset (n=6) patients, the course of the disease was as rapid as in the early-onset forms, when motor symptoms were present at disease onset, while patients with only cognitive symptoms at disease onset exhibited significantly milder disease progression, independent of their age at onset. A certain genotype-phenotype correlation was observed.
Conclusions:
In addition to age at onset, the type of first symptoms predicts the rate of disease progression in MLD. These findings are important for counselling and therapy.
Classification of evidence:
This study provides Class II evidence that in patients with MLD, age at onset and the type of first symptoms predict the rate of disease progression.
... Les monocytes issus de ces cellules peuvent se lier à la BHE comme macrophages périvasculaires et ainsi conduire à une correction dans le SNC (Système nerveux central)(Krivit et al.). Cependant, l'activité lysosomale normale de l'enzyme dans les HSC est trop faible pour apporter une correction croisée efficace et le rapport bénéfice/risque très bas a conduit à écarter cette approche(Peters & Steward 2003). Les HSC peuvent cependant être génétiquement modifiées par thérapie génique pour surexprimer l'enzyme thérapeutique (voir section suivante).Ces deux approches sont très invasives et coûteuses et peuvent impacter négativement la qualité de vie des patients en fonction de la durée du traitement(Wyatt et al. 2012). ...
L’un des principaux défis de la thérapie génique est d’identifier un vecteur sûr capable d’assurer un transfert efficace et une expression soutenue d’un gène d’intérêt thérapeutique dans les cellules cibles. L’émergence de vecteurs plasmidiques de nouvelles générations a permis d’atteindre ces objectifs et de considérer la thérapie génique non virale comme une alternative prometteuse aux vecteurs viraux pour le traitement de maladies génétiques ou acquises. Appartenant à ces nouvelles générations, les dérivés du vecteur pFAR4 sont des miniplasmides dépourvus de gène de résistance à un antibiotique. Leur propagation dans les cellules d’Escherichia coli est basée sur la suppression d’une mutation non-sens de type ambre introduite dans un gène essentiel de la souche productrice, permettant ainsi d’éliminer les risques associés à l’utilisation de gène de résistance à un antibiotique tout en diminuant la taille du vecteur. Le but de cette thèse est d’étudier le potentiel de ces vecteurs dans deux contextes de thérapie génique non virale : Dans une première approche, le potentiel du vecteur pFAR4 a été évalué pour l’expression d’un gène thérapeutique dans le foie de souris. Pour ce faire, un dérivé de ce vecteur exprimant le gène Sgsh à partir d’un promoteur spécifique des hépatocytes et codant la protéine sulfamidase, protéine défectueuse chez les patients souffrant de la maladie de Sanfilippo de type A, a été administré par injection hydrodynamique à des souris. Nous avons montré que le vecteur pFAR4 promeut dans le foie une expression élevée et soutenue de la sulfamidase, qui décline rapidement lorsque le gène Sgsh est administré par un vecteur contenant un gène de résistance à la kanamycine. Dans le cadre de cette étude, il a été établi que le profil d’expression obtenu avec le vecteur pFAR4 n’est pas lié à son insertion dans le génome des hépatocytes mais résulte, de par sa taille réduite, d’une protection contre les phénomènes d’extinction de transgène couramment observés in vivo avec les vecteurs conventionnels. Dans une seconde approche, le vecteur pFAR4 a été combiné à la technologie Sleeping Beauty (SB), dont l’un des constituants majeurs est la transposase hyperactive SB100X qui promeut la transposition d’un transgène, en l’excisant du plasmide qui le porte et en l’insérant dans le génome des cellules hôtes. Cette combinaison a été étudiée in vitro dans des cellules HeLa, en utilisant un transposon contenant soit le gène de résistance à la néomycine soit le gène codant la protéine fluorescente Vénus. Nous avons ainsi montré que le plasmide pFAR4 constituait un vecteur efficace pour les composants du système SB et que la combinaison pFAR4/SB conduisait à un taux de transgénèse augmenté par rapport à une association avec des plasmides conventionnels. Cette efficacité élevée résulte d’un niveau de transfection et d’un taux d’excision augmentés, tous deux favorisés par la taille réduite du plasmide. La combinaison pFAR4/SB devrait prochainement être utilisée pour transférer le gène codant le facteur anti-angiogénique PEDF (Pigment Epithelium-Derived Factor) à des cellules primaires de l’épithélium pigmentaire de la rétine ou de l’iris dans deux essais cliniques (Phase I/II) de thérapie génique ex vivo pour le traitement de la dégénérescence maculaire liée à l’âge (DMLA).
... These data seem highly relevant, not only for improved counseling of patients with MLD and their families but also, and especially, with respect to therapeutic approaches, whether these involve hematopoietic stem cell transplantation, enzyme replacement, or gene therapy. 9,[19][20][21] For all these approaches, an effect is reported primarily when implemented as early as possible during the disease course or even at a presymptomatic stage. On the basis of the data presented here, which indicate that the course of disease in patients with later onset is predicted by the type of first symptoms, individually tailored therapeutic decisions could be improved, depending on whether a more rapid or a more protracted course is to be expected. ...
... Complete donor chimerism is essential in preventing relapse in leukemia. However, it is not necessary for some benign hematological disorders as partial donor chimerism is sufficient to eradicate the manifestations of nonmalignant diseases, particularly immunedeficiency disorders and hemoglobinopathies [1][2][3]. Following graft kinetics is an integral part of post-transplant surveillance as we can now offer early withdrawal of immunosuppression with the addition of cellular therapy when required. ...
Donor lymphocyte infusion (DLI) is a form of cellular immunotherapy which is known to be effective in preventing relapse in leukemia by inducing graft versus leukemia (GVL) effect. In hematopoietic stem cell transplantation (HSCT) for benign hematological conditions including primary immune deficiency, mixed chimerism is seen with the use of reduced intensity conditioning. DLI can help prevent graft rejection by boosting the existing graft in these situations. There is scant data on the use of DLI in children who have undergone HSCT for benign hematological disorders. We present our case series with early withdrawal of immunosuppression and DLI as a means to mitigate relapse of leukemia and prevent graft rejection in mixed chimerism in children transplanted for benign hematological disorders. Donor lymphocyte infusion was given in a graded regimen with the cell dose of 1 × 105 CD3 cells/kg (1 × 104/kg in haploidentical transplant), 5 × 105 CD3 cells/kg, 1 × 106 CD3 cells/kg depending on the graft kinetics and the clinical status of the children. A total of fifty eight children including those with haploidentical donors underwent DLI with an overall survival of 81.1%. The use of fresh whole blood in very small aliquots from the donor has made this technique cost effective and an attractive form of immunotherapy.
... Hematopoietic cell transplantation (HCT) is a proven therapeutic approach for patients suffering from various hematologic and immunologic diseases (1). HCT is an immunotherapy procedure during which a healthy donor provides hematopoietic cells including stem and progenitor cells to a diseased host. ...
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapeutic approach for various hematologic and immunologic ailments. Despite the beneficial impact of allo-HCT, its adverse effects cause severe health concerns. After transplantation, recognition of host cells as foreign entities by donor T cells induces graft-vs.-host disease (GVHD). Activation, proliferation and trafficking of donor T cells to target organs and tissues are critical steps in the pathogenesis of GVHD. T cell activation is a synergistic process of T cell receptor (TCR) recognition of major histocompatibility complex (MHC)-anchored antigen and co-stimulatory/co-inhibitory signaling in the presence of cytokines. Most of the currently used therapeutic regimens for GVHD are based on inhibiting the allogeneic T cell response or T-cell depletion (TCD). However, the immunosuppressive drugs and TCD hamper the therapeutic potential of allo-HCT, resulting in attenuated graft-vs.-leukemia (GVL) effect as well as increased vulnerability to infection. In view of the drawback of overbroad immunosuppression, co-stimulatory, and co-inhibitory molecules are plausible targets for selective modulation of T cell activation and function that can improve the effectiveness of allo-HCT. Therefore, this review collates existing knowledge of T cell co-stimulation and co-inhibition with current research that may have the potential to provide novel approaches to cure GVHD without sacrificing the beneficial effects of allo-HCT.
... Transplantation remains the standard of care in younger patients with Hurler syndrome, early cerebral ALD, and asymptomatic late infantile or early juvenile metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy. BMT has also been used in other types of IEM, including, but not limited to, Hunter syndrome (MPS II), Maroteaux-Lamy syndrome (MPS VI), alpha-mannosidosis, and Wolman syndrome [21][22][23][24][25][26][27]. ...
Allogeneic Blood or Marrow Transplantation (BMT) is currently considered the standard-of-care for patients with specific Inborn Errors of Metabolism (IEM). However, there is a paucity of studies describing long-term survival and cause-specific late mortality after BMT in these patients with individual types of IEM. We studied 273 patients who had survived ≥2 years after allogeneic BMT for IEM between 1974 and 2014. The most prevalent IEM in our cohort were X-linked Adrenoleukodystrophy (ALD: 37.3%), Hurler syndrome (35.1%) and Metachromatic Leukodystrophy (MLD: 10.2%). Conditional on surviving ≥2y after BMT, the overall survival for the entire cohort was 85.5% (±2.4) and 73.5% (±3.7) at 10y and 20y, respectively. The cohort experienced a 29-fold increased risk of late death when compared with an age- and sex-matched general US population (95%CI, 22-38). The increased relative mortality was highest in the 2y to 5y period after BMT (Standardized Mortality Ratio, SMR=207; 95%CI, 130-308) and declined as time from BMT increased, but remained elevated ≥21y after BMT (SMR=9; 95%CI, 4-18). Sequelae from progression of primary disease were the most common cause of late mortality in this cohort (76%). Use of T-cell depleted grafts in patients with ALD and Hurler syndrome was a risk factor for late mortality. Younger age at BMT and use of busulfan and cyclosporine were protective in patients with Hurler syndrome. Our study demonstrates that ≥2y survivors of allogeneic BMT for IEM have a relatively favorable overall survival, although primary disease progression continues to be responsible for the majority of late deaths.
... The introduction of haematopoietic stem cells trasplantation in 1981 [4] improved the disease progression and patients survival in MPS I and IV. Successful engraftment provide a source of enzyme by donor cells resulting in improved cardiopulmonary function, decreased hepatosplenomegaly and improved neurologic status, and patients survive to adult age [5][6][7]. ...
Purpose:
Mucopolysaccharidosis (MPS) are rare inherited metabolic diseases, causing lysosomal storage of mucopolysaccharides; clinical presentation involves skeletal system and particularly the spine. Anomalies include developing kyphosis at thoracolumbar junction, that can causes nervous symptoms, and dens hypoplasia with associated atlantoaxial subluxation that can cause myelopathy. We present our experience in the treatment of spine pathology in MPS.
Methods:
Medical treatments of MPS seem to have little impact on spine disease: treatment of cervical instability often includes surgical decompression and stabilization, as in patient MPS1 that we present, while thoracic lumbar kyphosis is treated by bracing and, in severe cases, with surgery. Bracing is more effective in kyphosis under 40° Cobb. Our surgical cases with thoracic lumbar kyphosis over 40° Cobb, treatment include the first one ever described by only posterior approach with vertebrectomy in MPS and a case of lateral costo-transverse approach instrumented correction.
Results:
Surgical patients had no major complications after surgery and CT scan at follow-up showed complete fusion without loss of correction, even if in a cervical case we used an adult rigid instrumentation in a four year-and-six month-old girl (11 years follow-up) and in thoracic lumbar kyphosis case treated by vertebrectomy due to diminutive anatomy we positioned interbody cage in suboptimal position.
Conclusions:
Bracing is a viable treatment strategy in thoracic lumbar kyphosis and can obtain good clinical results at medium terms follow-up even if kyphosis deformity remains in radiographs. Surgical treatment is effective in severe evolving cases both at cervical and thoracic lumbar level, main difficulties arose from unavailability of dedicated instrumentation in very young patient, as even smallest devices available are often too big.
... In contrast to the temporary effect of a single round of ERT, hematopoietic cell transplantation (HCT) sometimes permanently restores the defective enzyme activity. Furthermore, HCT can treat tissues not accessible to ERT, but outcomes vary 19 . A second HCT imposes significant risk, so post-transplant enzyme supplementation may represent a safer alternative. ...
Certain recessively inherited diseases result from an enzyme deficiency within lysosomes. In mucopolysaccharidoses (MPS), a defect in glycosaminoglycan (GAG) degradation leads to GAG accumulation followed by progressive organ and multiple system dysfunctions. Current methods of GAG analysis used to diagnose and monitor the diseases lack sensitivity and throughput. Here we report a LC-MS method with accurate metabolite mass analysis for identifying and quantifying biomarkers for MPS type I without the need for extensive sample preparation. The method revealed 225 LC-MS features that were >1000-fold enriched in urine, plasma and tissue extracts from untreated MPS I mice compared to MPS I mice treated with iduronidase to correct the disorder. Levels of several trisaccharides were elevated >10000-fold. To validate the clinical relevance of our method, we confirmed the presence of these biomarkers in urine, plasma and cerebrospinal fluid from MPS I patients and assessed changes in their levels after treatment.
We describe the natural history of a three-month-old patient with Hunter Syndrome with hematopoietic stem cell transplant (HSCT) who developed recurrent diffuse alveolar hemorrhage (DAH) requiring extracorporeal membrane oxygenation (ECMO). The patient underwent HSCT with several complications, including veno-occlusive disease and DAH. He was managed with ECMO. Unfortunately, despite initial success he developed recurrent DAH and ultimately died. This is a novel report of this severe adverse event requiring ECMO following the use of HSCT in this rare patient population. We share the clinical strategies employed to address the complications associated with HSCT and the progression of his disease over his hospitalization.
CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec. This review assesses maribavir (Livtencity) 400 mg (2 tablets of 200 mg) twice daily resulting in a daily dose of 800 mg. Indication: Treatment of adults with post-transplant cytomegalovirus (CMV) infection or disease who are refractory (with or without genotypic resistance) to one or more prior antiviral therapies.
Background:
Acute graft-versus-host disease (aGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation (HSCT), occurring in 8% to 85% of paediatric recipients. Currently, the therapeutic mainstay for aGvHD is treatment with corticosteroids. However, there is no established standard treatment for steroid-refractory aGvHD. Extracorporeal photopheresis (ECP) is a type of immunomodulatory method amongst different therapeutic options that involves ex vivo collection of peripheral mononuclear cells, exposure to the photoactive agent 8-methoxypsoralen and ultraviolet-A radiation, and reinfusion of these treated blood cells to the patient. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and updated in 2015.
Objectives:
To evaluate the effectiveness and safety of ECP for the management of aGvHD in children and adolescents after HSCT.
Search methods:
We searched the Cochrane Register of Controlled Trials (CENTRAL), MEDLINE (PubMed) and Embase (Ovid) databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively.
Selection criteria:
We sought to include randomised controlled trials (RCTs) comparing ECP with or without standard treatment versus standard treatment alone in children and adolescents with aGvHD after HSCT.
Data collection and analysis:
Two review authors independently performed the study selection. We resolved disagreement in the selection of trials by consultation with a third review author.
Main results:
We identified no additional studies in the 2021 review update, so there are still no studies that meet the criteria for inclusion in this review.
Authors' conclusions:
The efficacy of ECP in the treatment of aGvHD in children and adolescents after HSCT is unknown, and its use should be restricted to within the context of RCTs. Such studies should address a comparison of ECP alone or in combination with standard treatment versus standard treatment alone. The 2021 review update brought about no additions to these conclusions.
Lysosomal storage diseases (LSDs) include a broad spectrum of 50 discrete genetic diseases, primarily due to defective lysosomal protein or their activity; in other scenarios, the irregularities arise from non-lysosomal activities such as lysosomal biogenesis or protein maturation. Gaucher disease is the most common disease, followed by Fabry disease. The prevalence of LSDs worldwide has reached epidemic proportions. Most LSDs are inherited as autosomal recessive traits due to mutations in genes encoding lysosomal proteins, which elicits a pathogenetic cascade. However, statistics indicate the incidence of each LSDs is very rare per se, ranging from 1 in 50,000 to 1 in 250,000 live births, but LSDs collectively are more common disorders (1:5000 live births). By far, various methodologies have been adopted besides systemic drug therapy. However, in many cases, surgeries are overused for preventing or alleviating the conditions. Conversely, the currently available therapies remain inadequate or lack effectiveness, especially in terms of patient compliance. Henceforth it remains crucial to explore various advanced therapies and delivery systems to treat better and lessen side effects. This chapter emphasizes potential targets available for LSDs and recent advances in delivery systems and subsequent novel therapies. Furthermore, we highlighted the significance of gene therapy, focusing on viral vectors; also, we stressed the future roadmap for gene therapy for LSDs. Additionally, current studies in clinical trials that potentially explored alleviating LSDs are briefly mentioned in this chapter.
Background:
Chronic graft-versus-host disease (cGvHD) is a major cause of morbidity and mortality after haematopoietic stem cell transplantation, occurring in 6% to 65% of the paediatric recipients. Currently, the therapeutic mainstay for cGvHD is treatment with corticosteroids, frequently combined with other immunosuppressive agents in people with steroid-refractory manifestations. There is no established standard treatment for steroid-refractory cGvHD. The therapeutic options for these patients include extracorporeal photopheresis (ECP), an immunomodulatory treatment that involves ex vivo collection of mononuclear cells from peripheral blood, exposure to the photoactive agent 8-methoxypsoralen, ultraviolet radiation and re-infusion of the processed cell product. The mechanisms of action of ECP are not completely understood. This is the second update of a Cochrane Review first published in 2014 and first updated in 2015.
Objectives:
To evaluate the effectiveness and safety of ECP for the management of cGvHD in children and adolescents after haematopoietic stem cell transplantation.
Search methods:
We searched the Cochrane Register of Controlled Trials (CENTRAL) (2021), MEDLINE (PubMed) and Embase databases from their inception to 25 January 2021. We searched the reference lists of potentially relevant studies without any language restrictions. We searched five conference proceedings and nine clinical trial registries on 9 November 2020 and 12 November 2020, respectively.
Selection criteria:
We aimed to include randomised controlled trials (RCTs) comparing ECP with or without alternative treatment versus alternative treatment alone in children and adolescents with cGvHD after haematopoietic stem cell transplantation.
Data collection and analysis:
Two review authors independently performed the study selection. We resolved disagreements in the selection of trials by consultation with a third review author.
Main results:
We found no studies meeting the criteria for inclusion in this 2021 review update.
Authors' conclusions:
We could not evaluate the efficacy of ECP in the treatment of cGvHD in children and adolescents after haematopoietic stem cell transplantation since the second review update again found no RCTs. Current recommendations are based on retrospective or observational studies only. Thus, ideally, ECP should be applied in the context of controlled trials only. However, performing RCTs in this population will be challenging due to the limited number of eligible participants, variable disease presentation and the lack of well-defined response criteria. International collaboration, multicentre trials and appropriate funding for such trials will be needed. If treatment decisions based on clinical data are made in favour of ECP, recipients should be carefully monitored for beneficial and harmful effects. In addition, efforts should be made to share this information with other clinicians, for example by setting up registries for children and adolescents treated with ECP.
Background
The natural history and genotype–phenotype correlation of Pelizaeus–Merzbacher disease (PMD) of Chinese patients has been rarely reported.
Method
Patients who met the criteria for PMD were enrolled in our study. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Natural history differences and genotype–phenotype correlations were analyzed.
Result
A total of 111 patients were enrolled in our follow-up study. The median follow-up interval was 53 m (1185). Among PMD patients, developmental delay was the most common sign, and nystagmus and hypotonia were the most common initial symptoms observed. A total of 78.4% of the patients were able to control their head, and 72.1% could speak words. However, few of the patients could stand (9.0%) or walk (4.5%) by themselves. Nystagmus improved in more than half of the patients, and hypotonia sometimes deteriorated to movement disorders. More PLP1 point mutations patients were categorized into severe group, while more patients with PLP1 duplications were categorized into mild group ( p < 0.001). Compared to patients in mild groups, those in the severe group had earlier disease onset and had acquired fewer skills at a later age.
Conclusion
PMD patients have early disease onset with nystagmus and hypotonia followed by decreased nystagmus and movement disorders, such as spasticit. Patients with PLP1 duplication were more likely to be categorized into the mild group, whereas patients with point mutations were more likely to be categorized into the severe group.
Although cross-correction was discovered more than 50 years ago, and held the promise of drastically improving disease management, still no cure exists for lysosomal storage diseases (LSDs). Cell therapies hold the potential to halt disease progression: either a subset of autologous cells can be ex vivo/ in vivo transfected with the functional gene or allogenic wild type stem cells can be transplanted. However, majority of cell-based attempts have been ineffective, due to the difficulties in reversing neuronal symptomatology, in finding appropriate gene transfection approaches, in inducing immune tolerance, reducing the risk of graft versus host disease (GVHD) when allogenic cells are used and that of immune response when engineered viruses are administered, coupled with a limited secretion and uptake of some enzymes. In the last decade, due to advances in our understanding of lysosomal biology and mechanisms of cross-correction, coupled with progresses in gene therapy, ongoing pre-clinical and clinical investigations have remarkably increased. Even gene editing approaches are currently under clinical experimentation. This review proposes to critically discuss and compare trends and advances in cell-based and gene therapy for LSDs. Systemic gene delivery and transplantation of allogenic stem cells will be initially discussed, whereas proposed brain targeting methods will be then critically outlined.
Background:
Gaucher disease (GD) is the most common lysosomal storage disease and requires long-term enzyme replacement therapy (ERT), which is costly and inconvenient for resource-limited countries such as Thailand. The authors present the case of a 1-year-old boy who was diagnosed with GD type 1 with a homozygous mutation at c.1448 T>C (L444P). He was treated with ERT and matched sibling hematopoietic stem cell transplantation (HSCT) was performed 6 months after the ERT was initiated. At a 3-year follow-up after the HSCT, he had full engraftment and the Lyso-GL1 levels were also at an acceptable level, which indicated disease remission. In conclusion, the authors suggest HSCT for long-term remission of GD in children.
Lysosomal storage disorders (LSDs) are a group of clinically heterogeneous disorders affecting the function of lysosomes and are characterized by an accumulation of undigested substrates within several cell types. In recent years there have been substantial advances in supportive care and drug treatment for some LSDs, leading to improved patient survival, as seen in Gaucher, Pompe and Fabry disease and some Mucopolysaccharidoses; however, many symptoms still persist. Thus it is now even more important to improve patients’ quality of life and reduce symptoms and comorbidities. One potential way of achieving this goal is through adjunct nutritional therapy, which is challenging as patients may be overweight with associated consequences, or malnourished, or underweight. Furthermore, drugs used to treat LSDs can modify the metabolic status and needs of patients. There are currently not enough data to make specific dietary recommendations for individual LSDs; however, suggestions can be made for managing clinical manifestations of the diseases, as well as treatment-associated adverse events. The metabolic and nutritional status of adult patients must be regularly assessed and individualized dietary plans may be created to cater to a patient’s specific needs. Damage to the autophagic process is a common feature in LSDs that is potentially sensitive to dietary manipulation and needs to be assessed in clinical studies.
Mucopolysaccharidosis type VII (MPS7) is a lysosomal storage disorder (LSD) resulting from mutations in the β-glucuronidase gene, leading to multiorgan dysfunction and fetal demise. While postnatal enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation have resulted in some phenotypic improvements, prenatal treatment might take advantage of a unique developmental window to penetrate the blood-brain barrier or induce tolerance to the missing protein, addressing two important shortcomings of postnatal therapy for multiple LSDs. We performed in utero ERT (IUERT) at E14.5 in MPS7 mice and improved survival of affected mice to birth. IUERT penetrated brain microglia, whereas postnatal administration did not, and neurological testing (after IUERT plus postnatal administration) showed decreased microglial inflammation and improved grip strength in treated mice. IUERT prevented antienzyme antibody development even after multiple repeated postnatal challenges. To test a more durable treatment strategy, we performed in utero hematopoietic stem cell transplantation (IUHCT) using congenic CX3C chemokine receptor 1–green fluorescent protein (CX3CR1-GFP) mice as donors, such that donor-derived microglia are identified by GFP expression. In wild-type recipients, hematopoietic chimerism resulted in microglial engraftment throughout the brain without irradiation or conditioning; the transcriptomes of donor and host microglia were similar. IUHCT in MPS7 mice enabled cross-correction of liver Kupffer cells and improved phenotype in multiple tissues. Engrafted microglia were seen in chimeric mice, with decreased inflammation near donor microglia. These results suggest that fetal therapy with IUERT and/or IUHCT could overcome the shortcomings of current treatment strategies to improve phenotype in MPS7 and other LSDs.
Background
Severe mucopolysaccharidosis type I (also known as Hurler syndrome) is a rare devasting recessive genetic disease caused by the deficiency of an enzyme. Hematopoietic stem cell transplant is the standard of care in the United States, usually conducted before the child is 3 years of age, but little is known about the continued medical and educational needs of the child after transplant. A greater understanding of the burden of illness on the primary caregiver is also needed. Therefore, this online survey sought to gather information on the burden of severe MPS I in the United States at least 1 year after transplant.
Results
Thirty-two respondents reported that children with severe MPS I have significant medical and educational needs after transplant. Healthcare resource use was frequent, especially in the outpatient setting specifically for bone, cardiac, and vision complications that were not relieved by HSCT. Twenty-five percent of the children had been hospitalized at least once in the last year and two had been hospitalized twice. The most common reasons for overnight hospitalizations included orthopedic surgeries and respiratory infections. Among children ages 5 and older, only 3 of 28 (11%) were able to attend school with no special support. While caregivers were generally satisfied with the healthcare services their child receives, 69% of working caregivers reported negative impact on their ability to conduct work tasks, and 54% of caregivers did not work so that they could care for the child.
Conclusions
Results suggest that severe MPS I children continue to require medical care and special support for education. Future research on the burden of illness on families affected by severe MPS I is needed to better understand total cost of care, and to identify therapies and interventions that reduce burden of illness. Future studies that compare cost of and access to health care in different countries may provide a more global view of the burden of MPS I.
Introduction 359 Rickets caused by vitamin D deficiency 359 Vitamin D-dependent rickets 361 Secondary vitamin D deficiency 363 Bone diseases with increased fracture rate: Osteopenia and osteoporosis 366 Key learning points 369 References 370 EVIDENCE SCORING OF THERAPY * Non-randomized controlled trials, cohort study etc.
Hereditary disorders of myelin formation or its maintenance comprise the “leukodystrophies,'' a term derived from leuko “white” and dystroph “defective nutrition” (1). These disorders are characterized based on biological and pathologic features rather than a common clinical syndrome. We will apply the term to monogenic disorders primarily affecting myelin formation or its upkeep, although the nosology of leukodystrophies is more complex (2).
Mucopolysaccharidosis (MPS) is a group of inherited conditions involving metabolic dysfunction. Lysosomal enzyme deficiency leads to the accumulation of glycosaminoglycan (GAG) resulting in systemic symptoms, and is categorized into seven types caused by deficiency in one of eleven different enzymes. The pathophysiological mechanism of these diseases has been investigated, indicating impaired autophagy in neuronal damage initiation, association of activated microglia and astrocytes with the neuroinflammatory processes, and involvement of tauopathy. A new inherited error of metabolism resulting in a multisystem disorder with features of the MPS was also identified. Additionally, new therapeutic methods are being developed that could improve conventional therapies, such as new recombinant enzymes that can penetrate the blood brain barrier, hematopoietic stem cell transplantation with reduced intensity conditioning, gene therapy using a viral vector system or gene editing, and substrate reduction therapy. In this review, we discuss the recent developments in MPS research and provide a framework for developing strategies.
Hematopoietic stem cell transplantation (HSCT) is a therapeutic option for many nonmalignant disorders (NMD) and is curative or prevents disease progression. Reduced-intensity conditioning (RIC) in HSCT for NMD may reduce regimen-related acute toxicities and late complications. Myeloablation is often replaced by immune suppression in RIC regimens to support donor engraftment. The pace of immune reconstitution after immune suppression by RIC regimens is influenced by agents used, donor source, and graft-versus-host disease prophylaxis/treatment. In a multicenter trial (NCT 00920972) of HSCT for NMD, a RIC regimen consisting of alemtuzumab, fludarabine, and melphalan was substituted for myeloablation. Alemtuzumab was administered early (days −21 to −19) to mitigate major lymphodepletion of the incoming graft and the risk of graft rejection. Immune reconstitution and infectious complications were prospectively monitored for 1-year post-HSCT. Seventy-one patients met inclusion criteria for this report and received marrow or peripheral blood stem cell transplants. Immune reconstitution and infections are reported for related donor (RD) and unrelated donor (URD) transplants at 3 time-points (100 days, 6 months, and 1 year post-HSCT). Natural killer cell recovery was rapid, and numbers normalized in both cohorts by day +100. Mean CD3, CD4, and CD8 T-lymphocyte numbers normalized by 6 months after RD HSCT and by 1 year in the URD group. CD4 and CD8 T-lymphocyte counts were significantly higher in patients who received RD HSCT at 6 months and at 1 year, respectively, post-HSCT compared with patients who received URD HSCT. The pace of CD19 B-cell recovery was markedly different between RD and URD cohorts. Mean B-cell numbers were normal by day 100 after RD HSCT but took 1 year post-HSCT to normalize in the URD cohort. Despite these differences in immune reconstitution, the timing and nature of infections did not differ between the groups, presumably because of comparable T-lymphocyte recovery. Immune reconstitution occurred at a faster pace than in prior reports using RIC with T-cell depletion. The incidence of infections was similar for both cohorts and occurred most frequently in the first 100 days post-HSCT. Viral and fungal infections occurred at a lower incidence in this cohort, with “early” alemtuzumab compared with regimens administering serotherapy in the peritransplantation period. Patients were susceptible to bacterial infections primarily in the first 100 days irrespective of donor source and had no increase in mortality from the same. The overall mortality rate from infections was 1.4% at 1 year. Close monitoring and prophylaxis against bacterial infections in the first 100 days post-HSCT is necessary but is followed by robust immune reconstitution, especially in the T-cell compartment.
Importance
Allogeneic hematopoietic stem cell transplantation is the standard intervention for childhood cerebral X-linked adrenoleukodystrophy. However, the pretransplant conditions, demyelination patterns, complications, and neurological outcomes of this therapy are not well characterized.
Objectives
To identify the risks to stable neurocognitive survival after hematopoietic stem cell transplantation and to describe subgroups of patients with distinct clinical long-term outcomes.
Design, Setting, and Participants
This case series analyzed the treatment and outcome of a cohort of 36 boys who underwent hematopoietic stem cell transplantation at Charité Universitätsmedizin Berlin, Germany, between January 1, 1997, and October 31, 2014. Case analysis was performed from January 1, 2016, through November 30, 2017. During this retrospective review, the adrenoleukodystrophy-disability rating score and the neurological function score were used. Demyelinating lesions in the brain were quantified by the Loes score.
Main Outcomes and Measures
Overall survival, survival without major functional disabilities, and event-free survival were analyzed. Patients’ clinical symptoms, demyelination patterns, and stem cell source were stratified.
Results
Of the 36 boys who underwent hematopoietic stem cell transplantation, the median (range) age was 7.2 (4.2-15.4) years; 18 were presymptomatic and 18 were symptomatic. Twenty-seven patients (75%) were alive at a median (interquartile range [IQR]) follow-up of 108 (40-157) months. Sixteen of 18 presymptomatic patients (89%) survived, and 13 (72%) had an event-free survival with a median (IQR) survival time of 49 (37-115) months. Among the symptomatic patients, 11 of 18 (61%) survived, but only 1 was an event-free survival (6%) (median [IQR] time, 9 [3-22] months). Of the 9 patients who received a bone marrow transplant from a matched family donor, all survived. Among the 36 patients, 6 disease-related deaths (17%) and 3 transplant-related deaths (8%) occurred. Deaths from disease progression (n = 6) occurred only in patients with demyelination patterns other than parieto-occipital. In total, 18 patients (50%) displayed limited parieto-occipital (Loes score <9) or frontal (Loes score <4) demyelination before transplant (favorable). None of these patients died of progressive disease or developed major functional disabilities, 15 of them were characterized by stable neuroimaging after the transplant, and event-free survival was 77% (95% CI, 60%-100%). In contrast, the other 18 patients with more extended parieto-occipital demyelination (n = 6), frontal involvement (n = 4), or other demyelination patterns (n = 8) progressed (unfavorable): 13 patients developed epilepsy and 10 developed major functional disabilities, and their event-free survival was 0%. This newly defined neuroimaging assessment correlated best with neurocognitive deterioration after transplant (hazard ratio, 16.7; 95% CI, 4.7-59.6).
Conclusions and Relevance
All patients with favorable neuroimaging who received matched bone marrow remained stable after transplant, while some of the other patients developed major functional disabilities. Newborn screening for the disease and regular neuroimaging are recommended, and patients who lack a matched bone marrow donor may need to find new therapeutic options.
Mucopolysaccharidosis II (MPS II—Hunter syndrome) is an X-linked lysosomal storage disorder caused by a deficiency in iduronate-2 sulfatase. Enzyme replacement therapy does not cross the blood–brain barrier (BBB), limiting the results in neurological forms of the disease. Another treatment option for MPS, hematopoietic stem cell transplantation (HSCT) has become the treatment of choice for the severe form of MPS I since it can preserve neurocognition when performed early in the course of the disease. Even though the intravenous therapy does not cross the BBB, it has become the recommended treatment for MPS II, and HSCT was not often indicated. In an attempt to understand why this treatment modality is rejected by most specialists as a treatment option for patients with Hunter syndrome, we sought to raise all HSCT cases already reported in the scientific literature. Databases used were Medline/PubMed, Lilacs/BVS Cochrane Library, DARE, SciELO, and SCOPUS. Different combinations of the terms “mucopolysaccharidosis II,” “Hunter syndrome,” “hematopoietic stem cell transplantation,” “bone marrow transplantation,” and “umbilical cord blood stem cell transplantation” were used. A total of 780 articles were found. After excluding redundant references and articles not related to the theme, 26 articles were included. A descriptive summary of each article is presented, and the main features are summed up. The clinical experience with HSCT in MPS II is small, and most of the available literature is outdated. The available data reveal poor patient selection criteria, varied conditioning regimens, distinct follow-up parameters, and post-HSCT outcomes of interest, making impossible to compare and generalize the results obtained. Recently, after the development of new conditioning protocols and techniques and the creation of bone marrow donor registries and umbilical cord banks, HSCT has become more secure and accessible. It seems now appropriate to reconsider HSCT as a treatment option for the neuronopathic form of MPS II.
Chloride channels play important roles in the plasma membrane and in intracellular organelles. Mice deficient for the ubiquitously expressed ClC-7 Cl− channel show severe osteopetrosis and retinal degeneration. Although osteoclasts are present in normal numbers, they fail to resorb bone because they cannot acidify the extracellular resorption lacuna. ClC-7 resides in late endosomal and lysosomal compartments. In osteoclasts, it is highly expressed in the ruffled membrane, formed by the fusion of H+-ATPase-containing vesicles, that secretes protons into the lacuna. We also identified CLCN7 mutations in a patient with human infantile malignant osteopetrosis. We conclude that ClC-7 provides the chloride conductance required for an efficient proton pumping by the H+-ATPase of the osteoclast ruffled membrane.
A 12-year-old girl with Sly disease (mucopolysaccharidosis VII; beta-glucuronidase deficiency), who is homozygous for the A619V mutation, had a successful allogeneic BMT, donored by an HLA-identical unrelated female to replace the deficient enzyme. Within 5 months after BMT, the enzyme activity of the recipient's lymphocytes increased to normal range. No signs of acute or chronic GVHD were observed. For the successive 31 months post-BMT, beta-glucuronidase activity in her lymphocytes was maintained at almost normal levels and excretion of glycosaminoglycans in the urine was greatly diminished. Ultrastructural findings demonstrated no abnormal vacuoles and inclusion bodies in the cytoplasm of her rectal mucosal cells. Coincident with the restoration of the enzyme activity, clinical improvement was dramatic. Especially notable were improvements in motor function. The patient was able to walk alone for a long time without aid, and she even became able to ride a bicycle and take a bath. In addition, recurrent infections of the upper respiratory tract and the middle ears decreased in frequency and severity, and dyspnea on exertion, severe snoring and vertigo have substantially improved. Thus, allogeneic BMT in this patient produced a better quality of life and provided a more promising outlook.
Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease.
The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed.
Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.
Bone marrow transplantation (BMT) was performed in 10 patients with Hunter disease (mucopolysaccharidosis type II, iduronate‐2‐sulphatase deficiency). The donor was an HLA‐identical sibling in 2 cases, an HLA‐nonidentical relative in 6 cases, a volunteer unrelated donor in 1 case, and details were not available in 1 case. Only three patients have survived for more than 7 years post BMT; however, this high mortality probably resulted from poor donor selection. In two, there has been a steady progression of physical disability and mental handicap. One patient has maintained normal intellectual development, with only mild physical disability. It is possible that BMT may be useful in selected patients with MPS II.
Between 1980 and 1988, displacement bone-marrow transplantation was performed on 25 children with Hurler's syndrome (type-1 mucopolysaccharidosis). We describe the musculoskeletal development of 11 of the 12 surviving children and the orthopaedic procedures undertaken to treat progressive thoracolumbar kyphosis, hip subluxation and carpal tunnel syndrome. We found abnormal bone modelling, focal failures of ossification and an avascular disorder of the femoral head in every patient and offer an explanation for these phenomena. Increasing valgus deformity of the knees and progressive generalised myopathy caused loss of mobility as the children entered adolescence. The benefit of bone-marrow transplantation as a treatment for the skeletal disorders of Hurler's syndrome is limited by the poor penetration of the musculoskeletal tissues by the enzyme derived from the leucocytes.
Treatment and potential cure of lysosomal and peroxisomal diseases, heretofore considered fatal, has become a reality during the past decade. Bone marrow transplantation, (BMT), has provided a method for replacement of the disease-causing enzyme deficiency. Cells derived from the donor marrow continue to provide enzyme indefinitely. Several scores of patients with diseases as diverse as metachromatic leukodystrophy, adrenoleukodystrophy, globoid cell leukodystrophy, Hurler syndrome (MPS I-H), Maroteaux-Lamy (MPS VI) Gaucher disease, and fucosidosis have been successfully treated following long-term engraftment. Central nervous system (CNS) manifestations are also prevented or ameliorated in animal models of these diseases following engraftment from normal donors. The microglial cell system has been considered to be the most likely vehicle for enzyme activity following bone marrow engraftment. Microglia in the mature animal or human are derived from the newly engrafted bone marrow. Graft-v-host disease activation of the microglia is also of importance. This article will summarize some of the pertinent literature relative to the role of microglia in such transplant processes.
Maroteaux-Lamy syndrome is a mucopolysaccharidosis due to an enzymatic deficiency of arylsulfatase B (N-acetylgalactosamine-4-sulfatase) (ASB; EC 3.1.6.1) in the leukocytes, fibroblasts and tissues. This storage disease is inherited as an autosomal recessive. The clinical description includes presentation with hepatosplenomegaly, dysostosis multiplex with later development of pulmonary and cardiac insufficiency. Bone marrow transplantation has successfully corrected the enzymatic defect in 6 patients. The gene for the arylsulfatase B has been characterized and cloned. A vector has been constructed into which the normal gene has been inserted. The normal gene with the vector has been introduced into fibroblasts from Maroteaux-Lamy patients and normal, and even greater than normal, amounts of arylsulfatase B have been produced. Previously, the experimental feline model of arylsulfatase B has been successfully treated by allogeneic bone marrow transplantation. The material presented in this article includes a review of the above data and a consideration of therapeutic approaches for the future.
X linked adrenoleucodystrophy (X-ALD) is considered to be a rare cause of Addison's disease, although several small series suggest a high incidence in young Addisonian males. A survey in the south west of England identified 12 male patients diagnosed with Addison's disease in the period 1987–99. In 10 of these (83%) X-ALD was the underlying cause; the other two were of autoimmune aetiology. Five boys had developed Addison's disease subsequent to the diagnosis of X-ALD. Of the remaining five, in three boys the diagnosis of X-ALD was considerably delayed (by six months to two years from that of Addison's disease) and in two it was only made as a result of this survey. We also identified a patient who presented with Addison's disease at the age of 5 years but was only diagnosed as having X-ALD at the age of 34 years; in the interim his diagnosis of adrenomyeloneuropathy had been missed. Our experience highlights the absolute necessity of measuring very long chain fatty acids in all males with idiopathic Addison's disease.
A one-year-old boy with type I H mucopoly saccharidosis (Hurler's disease) was given a bone-marrow transplant (BMT) from his mother in an attempt to replace the deficient enzyme, alpha-L-iduronidase (iduronidase). There is definite evidence of engraftment, the enzyme activity of the recipient's leucocytes reaching heterozygote levels within 37 days of the BMT. Graft-versus-host disease (GVHD) developed but was partially controlled by steroids. From 3-4 months after graft until the present (13 months after the graft) iduronidase activity has been present in the serum and the urine and there has been evidence of considerable degradation of glycosaminoglycans excreted in the urine. The hepatosplenomegaly has disappeared, corneal clouding has cleared, and deterioration in the child's development seems to have been arrested.
Long-term effects of bone marrow transplantation (BMT) were evaluated in patients with I-cell disease, metachromatic leukodystrophy (MLD), Maroteaux-Lamy syndrome or Hunter syndrome (mild form). Donors were human leukocyte antigen (HLA)-matched siblings, and the follow-up periods were 24–71 months after BMT. The enzyme activities were increased in leukocytes, plasma or liver tissues compared with pre-BMT levels. A patient with I-cell disease acquired development of 4–8 month old infants and showed no further progression in cardiac dysfunctions. A patient with MLD showed a decelerated disease progression and an improved peripheral neuropathy, but progressive brain atrophy was not prevented. Patients with Maroteaux-Lamy syndrome or Hunter syndrome showed improvements in hepatomegaly, joint contractures, short stature and tight skin, and this greatly increased their quality of life. These results indicated that the long-term therapeutic effects achieved by BMT were subject to multiple factors including biochemical improvements, a reversibility of affected tissues, or advanced states of disease and central nervous system impairments in inborn errors of metabolism.
We report successful bone marrow transplantation in a child with a severe form of α-mannosidosis, type I. There was complete resolution of the recurrent sinopulmonary disease and organomegaly, improvement in the bony disease, and stabilization of neurocognitive function. (J Pediatr 1998;133: 282-5)
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Severe coronary artery disease may occur early in the course of mucopolysaccharidosis. The authors present radiologic, scintigraphic, and pathologic findings in five patients with Hurler syndrome. Thallium-201 myocardial scintigraphy and selective coronary angiography obtained within 2 days to 6 months were correlated in five patients. Postmortem examination of the coronary arteries was obtained in one patient within hours of angiography. Interobserver agreement on grading of scintigraphic abnormalities was poor. Nonspecific findings on TI-201 studies included septal abnormalities in all five patients. Scintigraphic findings were corroborated by angiography and postmortem results in only 3 of 5 patients. Our findings suggest that resting TI-201 scintigraphy has limited value in the detection of coronary artery disease in patients with Hurler syndrome.
The International Storage Disease Collaborative Study Group has evaluated the effectiveness of hematopoietic cell transplant (HCT) to halt the progressive neurologic deterioration, dementia, and early death of cerebral X-adrenoleukodystrophy (CXALD) in 126 patients (? donor: 3) from July 1982 to January 1999.
HCT can achieve neurologic and neuropsychologic stabilization as well as preservation of life in boys with CXALD especially when performed early in the disease course. A centralized HCT CXALD database is needed so that clinical trials can be performed.
The cerebro-hepato-renal syndrome is a rare familial malady with cerebral, renal, and skeletal abnormalities, severe hypotonia,
cirrhosis, iron and lipid storage, and death within 6 months. Correlated electron microscopic, histochemical, and biochemical
studies demonstrate defects in two oxidative organelles. Peroxisomes cannot be found in hepatocytes and renal proximal tubules.
In hepatocytes and cortical astrocytes, mitochondria are distorted in their appearance and glycogen stores are increased.
Oxygen consumnption of brain and liver mitochondrial preparations with succinate and with substrates reducing nicotinamide
adenine dinucleotide is markedly diminished, but the consumption is normal with ascorbate and tetramethylphenylenediamine,
which suggests a defect in electron transport prior to the cytochromes. Histochemical studies of mitochondrial oxidation point
to a defect between the succinate dehydrogenase flavoprotein and coenzyme Q, possibly in the region of nonheme iron protein.
Patients with the cerebrohepatorenal syndrome of Zellweger lack peroxisomes and certain peroxisomal enzymes such as dihydroxyacetone phosphate acyltransferase in their tissues. Deficiency of this enzyme, which is necessary for glycerol ether lipid synthesis, provides a biochemical method for recognizing patients with subtle manifestations of Zellweger syndrome and suggests the utility of exogenous ether lipid precursors as a therapeutic strategy for these children. We describe the results of glycerol ether lipid supplementation to two children, one with classic Zellweger syndrome and 9% of control fibroblast dihydroxyacetone phosphate acyltransferase activity, and one with mild facial manifestations, wide sutures, hypotonia, developmental delay, hepatomegaly, peripheral retinal pigmentation, and 50% of control fibroblast dihydroxyacetone phosphate acyltransferase activity. An increase in erythrocyte plasmalogen levels following therapy was clearly demonstrated in the milder patient, and neither patient showed evidence of toxicity. Evaluation of therapy by comparison to the usual clinical course of Zellweger syndrome was not helpful because of the variability and incomplete documentation of 90 previously reported cases. The literature survey did provide criteria for classic Zellweger syndrome, which include hypotonia with or without deformation of limbs, large fontanels and split sutures, prominent forehead, flattened facial profile with hypoplastic supraorbital ridges, anteverted nares, highly arched palate, cryptorchidism or labial hypoplasia, hepatomegaly or elevated liver enzymes, peripheral pigmentation of the retina, renal cortical cysts, and characteristic neuropathology involving decreased myelinization, abnormal neuronal migration, and sudanophilic macrophages. Less severe patients, as exemplified by our case 2 and others from the literature, will not have all the classic features and can be recognized only by a growing panel of biochemical indicators. Our patient studies illustrate the complexity of designing comprehensive therapy for Zellweger-like conditions, suggest other diseases that may involve peroxisomal alterations, and emphasize the need for multicenter, collaborative studies to evaluate biochemical heterogeneity and therapy of peroxisomal disorders.
A girl of non-Jewish origin, with non-contributory family history, at the age of 3 developed progressive mental deterioration, an ataxic-spastic syndrome and died in a decerebrate state at the age of 18 10/12 years. Neuropathological examination disclosed severe discontinuous-subtotal demyelination and diffuse sclerosis of the cerebral and cerebellar white matter with some small myelin islets and sparing of the subcortical arcuate fibres as well as of the deeper myelinated regions. There were remarkably sparse residua of orthochromatic myelin breakdown chiefly of the fixed type. The axons were preserved. Additional atrophic lesions of the thalamus and cerebellar folia were considered to be of anoxic origin. This sporadic case is suggested to represent a transitional form between the classical and the co-natal (Seitelberger) type of Pelizaeus-Merzbacher Disease.Ein Mdchen aus gesunder, nicht-jdischer Familie erkrankte im 3. Lebensjahr mit schubfrmig-progressiver psychischer Retardierung, cerebellar-spastischem Syndrom und starb mit 18 10/12 Jahren in einem Decerebrationszustand. Neuropathologisch fand sich eine schwere diskontinuierlich-subtotale Entmarkung und Sklerose im Gro- und Kleinhirn mit wenigen erhaltenen Markinseln, intakten U-Fasern und tiefen Markstrukturen bei nur diskretem fixen orthochromatischen Abbau. Eine symmetrische Thalamusatrophie und Kleinhirnlppchensklerose wird als Anoxieschaden aufgefat. Die sporadische Beobachtung wird der bergangsform zwischen klassischem und konnatalem Typ der Pelizaeus-Merzbacherschen Krankheit zugeordnet.
The motor neuron degeneration (mnd) mouse has been documented to accumulate proteolipid and thus is a model of neuronal ceroid lipofuscinosis [Dunn, W.A., Raizada, M.K., Vogt, E.S. and Brown, E.A., Int. J. Dev. Neurosci., 12 (1994) 185–196; Faust, J.R., Rodman, J.S., Daniel, P.F., Dice, J.F. and Bronson, R.T., J. Biol. Chem., 269 (1994) 10150–10155]. While accumulation of proteolipid in the hippocampus of chimeric mice composed of mnd and +/+ cells was found to be proportional to the contribution of mnd in the brain, accumulation within individual cells was the same for cells from chimeric and age-matched mnd mice. Bone marrow transplantation was used to altering the milieu of circulating factors to determine whether this might modify the disease phenotype in mnd mice. Transplantation of bone marrow in neonatal or young mice did not reduce the age-associated accumulation of proteolipid within hippocampal neurons. The results of these experiments indicate that mnd results in a cell autonomous defect.
Globoid-cell leukodystrophy is caused by a deficiency of galactocerebrosidase, which results in progressive central nervous system deterioration. We investigated whether allogeneic hematopoietic stem-cell transplantation can provide a source of leukocyte galactocerebrosidase and thereby prevent the decline of central nervous system function in patients with the disease.
Five children with globoid-cell leukodystrophy (one with the infantile type and four with late-onset disease) were treated with allogeneic hematopoietic stem-cell transplantation. Measurement of leukocyte galactocerebrosidase levels, neurologic examinations, neuropsychological tests, magnetic resonance imaging of the central nervous system, cerebrospinal fluid protein assays, and neurophysiologic measurements were performed before and after transplantation, with follow-up ranging from one to nine years.
Engraftment of donor-derived hematopoietic cells occurred in all patients and was followed by restoration of normal leukocyte galactocerebrosidase levels. In the four patients with late-onset disease, the central nervous system deterioration was reversed, and in the patient with the infantile form of the disease, signs and symptoms have not appeared. Magnetic resonance imaging showed a decrease in signal intensity in the three patients with late-onset disease who were assessed both before and after transplantation. Abnormalities in cerebrospinal fluid total protein levels were corrected in three patients with late-onset disease and substantially reduced in the patient with the infantile form.
Central nervous system manifestations of globoid-cell leukodystrophy can be reversed by allogeneic hematopoietic stem-cell transplantation.
Untreated patients with Hurler syndrome (MPSIH) experience progressive neurologic deterioration and early death. Allogeneic bone marrow transplantation (BMT) ameliorates or halts this course. The Storage Disease Collaborative Study Group was formed to evaluate the effectiveness and toxicity of BMT. Effectiveness was defined as engrafted survival with continuing cognitive development. Fifty-four patients deficient in leukocyte alpha-L-iduronidase enzyme activity (median age, 1.8 years; range, 0.4 to 7.9) received high-dose chemotherapy with or without irradiation and BMT from HLA-genotypically identical sibling (GIS) or HLA-haploidentical related (HIR) donors between September 16, 1983 and July 14, 1995; all children were included in this report. Thirty-nine of 54 patients (72%) engrafted following the first BMT. The probability of grade II to IV acute graft-versus-host disease (GVHD) at 100 days was 32% for GIS and 55% for HIR patients. The probability of extensive chronic GVHD was 0% for GIS and 24% for HIR patients. The actuarial probability of survival at 5 years was 64% for all patients, 75% for GIS patients, 53% for HIR patients, and 53% for patients with donor marrow engraftment. The baseline Mental Developmental Index (MDI) was examined both for children less than and greater than 24 months of age at BMT. Children transplanted before 24 months had a mean baseline MDI of 78, while those transplanted after 24 months had a mean baseline MDI of 63 (P = . 0002). Both baseline and post-BMT neuropsychologic data were available for 26 of 30 engrafted survivors. Of 14 patients transplanted before 24 months of age, nine demonstrated developmental trajectories that were normal or somewhat slower than normal. In contrast, of 12 patients transplanted after 24 months of age, only three showed developmental trajectories that were normal or somewhat slower than normal (P = .01). For children with a baseline MDI greater than 70, there was a significant correlation between the MDI at follow-up study and leukocyte alpha-L-iduronidase enzyme activity (P = .02). Children were more likely to maintain normal cognitive development if they were fully engrafted following BMT from a donor with homozygous normal leukocyte alpha-L-iduronidase enzyme activity. Children who developed acute GVHD of grade II or worse had significantly poorer cognitive outcomes (P < .009). No difference in the post-BMT MDI was observed between patients whose preparative therapies did (n = 10; radiation dose, 300 to 1,400 cGy) or did not (n = 16) include radiation. We conclude that MPSIH patients, particularly those less than 24 months of age with a baseline MDI greater than 70, can achieve a favorable long-term outcome with continuing cognitive development and prolonged survival after successful BMT from a related donor with homozygous normal enzyme activity.
Allogeneic bone marrow transplantation was performed on twins with Sanfilippo B disease. They were the first two patients with this disorder to undergo the procedure. There was definite evidence of engraftment as shown by conversion to donor blood group antigen and tissue type, and increased leukocyte alpha-glucosaminidase activity. Nine years post transplant, neither twin is as handicapped as her untreated brothers were at the same age, although in one twin hyperactivity and behavioural problems, characteristic of the disorder, are present. Details of the twins' intellectual development and growth, their alpha-glucosaminidase activity and urinary glycosaminoglycan excretion are reported.
Serial liver biopsies were obtained in 20 patients undergoing bone marrow transplantation (BMT) for mucopolysaccharidosis (MPS). The 13 patients with MPS I, one with MPS II, four with MPS III, and two with MPS VI underwent liver biopsy prior to and from 1 to 37 months after BMT. The amount of accumulated glycosaminoglycan (GAG) was assessed by semiquantitation of Kupffer cell staining with colloidal iron and by counting the number of hepatocellular GAG-containing lysosomes in electron micrographs. Eleven of 13 patients with MPS I achieved engraftment, and 10 of the 11 cleared the Kupffer cells and hepatocytes of GAG by 3 to 19 months post-BMT. Two patients with autologous recovery demonstrated persistent hepatocyte inclusions. The three patients with MPS II and MPS VI engrafted and showed clearance of hepatocyte and Kupffer cell GAG by 7 months after BMT. All four patients with MPS III engrafted. Although the Kupffer cells in these patients were cleared of GAG by 12 months after BMT, hepatocellular inclusions persisted in all four. For MPS I, II and VI, donor engraftment was associated with resolution of lysosomal storage material in donor-derived Kupffer cells and untransplanted hepatocytes, indicative of transcellular metabolic correction. Failure of hepatocyte clearance in one case of MPS I and all patients with MPS III suggested a diminished capacity of the graft-derived enzyme to enter the hepatocyte lysosomes in these patients.
Alglucerase (Ceredase) provides effective enzyme-replacement treatment for patients with Gaucher's disease, but at the usually recommended dose of 60 U per kilogram of body weight every two weeks (130 U per kilogram per month), it costs $382,200 per year for a 70-kg patient. Theoretical considerations suggest that more frequent administration would be more efficient.
Fourteen patients with type 1 Gaucher's disease that was moderately severe to severe were given 30 U of alglucerase per kilogram per month, in divided doses given either daily or three times weekly, or 120 U given three times weekly. The effect of the treatment on the size of the liver and spleen and on blood counts was compared with published data on patients who received a total dose four to five times as large as the lower dose we used and who received treatment every two weeks.
The response to 30 U of alglucerase per kilogram per month, fractionated into three or seven doses weekly, was approximately the same as that reported after the administration every two weeks of a dose four or five times as large, given in the large infusions usually recommended. A fourfold increase in the dose given three times weekly, from 2.3 to 9.2 U per kilogram, did not substantially increase the rate of improvement.
The treatment of Gaucher's disease with smaller total doses of alglucerase given more frequently yields satisfactory results. A dose of 2.3 U per kilogram three times weekly yields major financial benefits with no sacrifice of therapeutic effect. Even taking into account the increased ancillary costs of more frequent administration, this method of administering alglucerase reduces the annual cost of the drug for a 70-kg patient to about $100,000.
Wolman's disease is a fatal disorder characterized by absence of acid lipase and accumulation of cholesterol esters. Inanition due to malabsorption and intractable diarrhea has been the most prominent cause of early demise within the first year. Further complications have included cirrhosis and pulmonary failure due to cholesterol ester storage in respective cells. Although sustained caloric balance can be maintained by total parenteral nutrition, this has not altered the eventual course of disease. The acid lipase deficiency in leucocytes in Wolman's disease can be corrected subsequent to bone marrow transplantation. This has proven to be the case in two patients so transplanted. In two other patients, engraftment was not obtained following bone marrow transplantation. The concept of treatment of Wolman's disease by providing normalization of the acid lipase activity by allogeneic bone marrow transplantation remains valid. However, improvement of bone marrow transplant procedure needs to be implemented since pre-existing morbid pathology enhances toxicity and may prevent engraftment. Alternative modifications for accomplishing sustained engraftment without toxicity need to be examined. Other potential therapies need to be inspected in treatment of patients with Wolman's disease. The capability of reducing cellular cholesterol synthesis by use of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, is now available. In the future, isolation and purification of acid lipase will allow for direct infusion of missing enzyme. The molecular biology now known concerning acid lipase gene holds promise for the future for recombinant manufacturing of acid lipase. And, gene therapy with its use of autologous bone marrow transplantation will be tried in future.(ABSTRACT TRUNCATED AT 250 WORDS)
Hurler syndrome (mucopolysaccharidosis type I-H) is an inherited lysosomal storage disease characterized by the widespread accumulation of mucopolysaccharide in tissues throughout the body.1 Although severe coronary artery luminal narrowing has been documented by postmortem examination of the heart of patients with Hurler syndrome,2 the only reported study in which coronary angiography was performed stated that the coronary arteries appeared normal.3 As part of an ongoing protocol at our institution, selective coronary angiography was performed in children with Hurler syndrome before bone marrow transplantation. The subsequent availability of postmortem material from 3 such patients has allowed us to perform a retrospective analysis of the usefulness of selective coronary angiography in detecting the presence of coronary artery disease in patients with the Hurler syndrome.
Gaucher disease is the most prevalent lysosomal storage disease. This autosomal recessive disease is caused by the defective activity of the enzyme acid beta-glucosidase and the resultant accumulation of glucosylceramide primarily within cells of the reticuloendothelial system. Because the primary manifestations of Gaucher disease are due to involvement of monocyte/macrophage-derived cells, this disease is thought to be an excellent candidate for curative intervention via bone marrow transplantation (BMT). A Hispanic female with subacute neuronopathic Gaucher disease and rapidly progressing visceral manifestations underwent BMT at 23 mo of age using her histocompatible normal brother as the donor. Cytogenetic analyses demonstrated complete, stable engraftment by 1 mo post-BMT. During the subsequent 24 mo, clinical, biochemical, enzymatic, and histologic studies demonstrated nearly complete correction in the viscera. Her neuropathic manifestations did not progress. Complete reconstitution of enzymatic activity in peripheral blood leukocytes was achieved by 1 mo. Cytogenetic analyses demonstrated complete engraftment by d 79 and nearly complete loss of bone marrow Gaucher cells was observed by 8 mo. Plasma glucosylceramide levels normalized by 8-12 mo. Nearly coincident improvements in hepatic size, enzyme levels, and histology were found by 12-24 mo post-BMT. Fatal sepsis occurred at 24 mo post-BMT. Autopsy revealed sparse Gaucher cells in clusters in the liver, lymph nodes, and lungs as well as the lack of periadventitial Gaucher cells surrounding brain vessels. The findings provide the time course and rationale for studies directed to gene therapy via BMT for this disease after introduction of acid beta-glucosidase gene constructs into autologous pluripotent stem cells of selected Gaucher disease patients.
The Norrbottnian type of Gaucher disease is a well defined nosological entity with a characteristic course and clinical manifestations. The disease is caused by a deficiency of the enzyme glucosylceramidase (cerebroside-beta-glucosidase). Studies of genomic DNA and cDNA encoding the enzyme show a single base substitution in exon 10 in the Norrbottnian patients. The enzymic lesion causes an accumulation of glucosylceramide and glucosylsphingosine in cells of the monocyte-macrophage system, particularly in spleen, liver and bone marrow. Early splenectomy results in severe symptoms from skeleton and CNS, owing to accelerated storage of glucosylceramide in these organs. Bone marrow transplantation had a life-saving effect and seems to be the method of choice for beneficial enzyme replacement therapy.
This article has no abstract; the first 100 words appear below.
METACHROMATIC leukodystrophy of the late infantile type, an autosomal recessive inherited disorder caused by a deficiency of arylsulfatase A activity, is characterized by progressive mental regression, loss of speech, quadriparesis, peripheral neuropathy, and death within a few years of onset.¹ We describe a 10-year-old girl with metachromatic leukodystrophy in whom neurophysiologic function and sulfatide metabolism had improved after she received a bone marrow transplant five years before. These results may encourage the use of bone marrow transplantation in other patients with metachromatic leukodystrophy early in the course of the disease, when the degree of central nervous system impairment and the . . .
Supported by a grant (CA-21737) from the National Cancer Institute and by grants from the Children's Cancer Research Fund, the Minnesota Medical Foundation, Graduate School, the Eagles (KROC), and the Bone Marrow Research Fund.
We are indebted to Ms. Sheryl Frankel for help in preparing the manuscript, to Dr. Toni Moran for growth hormone studies, to Dr. Chester Whitley for support and encouragement, to Dr. Ben Lee for reviewing radiographic studies, and to the house staff and nursing staff for their participation.
Source Information
From the Bone Marrow Transplantation Program, Department of Pediatrics (W. Krivit, N.K.C.R., J.H.K.), the Division of Pediatric Neurology (E.S., W. Kennedy, M.L., L.L., S.S.), the Department of Ophthalmology (C.G.S.), and the Department of Laboratory Medicine and Pathology (M.Y.T., J.H.K.), University of Minnesota, Minneapolis; the Department of Medical Genetics (D.A.W.), Jefferson Medical College, Philadelphia; Department of Veterans Affairs (J.K.Y.), Pittsburgh; and the New England Medical Center (E.K.), Boston. Address reprint requests to Dr. Krivit at the University of Minnesota, 1252 Ingerson Rd., St. Paul, MN 55112.
Allogeneic bone marrow transplantation was carried out in an 81-day-old Portuguese water dog with GM1 gangliosidosis using a DLA identical sibling as donor. Engraftment was complete and beta-galactosidase activity in leukocytes of the transplanted dog were similar to those in the donor. Over the next 2.5 months neurological deterioration in the transplanted dog was similar to that in untreated dogs with GM1 gangliosidosis. Cerebral ganglioside GM1 concentrations were not diminished by bone marrow transplantation and cerebral beta-galactosidase activity was negligible. We conclude that allogeneic bone marrow transplantation early in life is ineffective in canine GM1 gangliosidosis.
We investigated whether the course of canine ceroid lipofuscinosis (CCL), a model of Batten's disease in man, was affected by allogeneic bone marrow transplantation. Four English setters with CCL, 4 1/2 months of age, were given 9.2 Gy of total body irradiation, followed by the infusion of bone marrow cells from healthy DLA identical sibling donors. All transplanted dogs had complete hematologic reconstitution. However, at 12-13 months posttransplant, all dogs developed characteristic and progressive signs of CCL. Autopsies revealed cerebral atrophy and findings of ceroid storage not different from those in non-transplanted controls. These findings suggest that bone marrow cells do not contain or release the gene product(s) necessary to correct the disease. It appears unlikely that with our current knowledge, allogeneic marrow transplantation would be beneficial in the treatment of Batten's disease.
Three children, two girls and one boy, with Gaucher disease of the Norrbottnian type were treated by allogeneic bone marrow transplantation (BMT). Two of the donors were heterozygotes for Gaucher disease, and the third did not carry the gene. Engraftment was achieved in all three children but the boy became a chimera. The children have been followed from 1.5 to 6 years after transplantation. In each case the outcome was favourable, and in two children (patients 1 and 3) the BMT has been life saving. In all three cases a positive biochemical effect was apparent. Almost all biochemical parameters normalized within one year. The authors conclude that BMT is the treatment of choice in severe cases of Gaucher disease. BMT should be considered early in the course of disease and vigorous efforts made to find a suitable donor.
Metabolic correction and physiologic response were evaluated after bone marrow transplantation in mucopolysaccharidosis. Eleven patients were prospectively evaluated to determine the effect of bone marrow transplantation on the progressive ocular manifestations of these disorders. Follow-up of 0.6 to 2.8 years after successful donor stem cell engraftment showed that some patients had slow clearing of the corneal clouding, reduction of intracytoplasmic inclusions in the conjunctiva, resolution of optic nerve edema, and stabilized or improved retinal function as determined by electroretinography. These preliminary results suggest that early bone marrow transplantation may alter some of the progressive ophthalmic characteristics of the mucopolysaccharidoses. Long-term follow-up is necessary to determine if these early alterations in the ocular features are predictive of a prolonged functional improvement in the visual status.
We examined the lysosomal enzyme levels in tear fluids from a patient with I-cell disease after treatment by bone marrow transplantation. Acid phosphatase, beta-D-glucuronidase, N-acetyl-beta-D-glucosaminidase, alpha-L-fucosidase and alpha-D-mannosidase activities were reduced to normal or nearly normal levels after the treatment. We believe that the measurement of tear enzyme levels in I-cell disease is useful for knowing the efficacy of the bone marrow transplantation.
In this retrospective analysis of allogeneic bone-marrow transplantation (BMT) carried out between 1969 and 1985 at fourteen European centres in 162 patients with sixteen different types of inherited immunodeficiencies and osteopetrosis, the overall survival with functional grafts was 51.7% (85 patients), with a minimum follow-up of 5 months. In patients with severe combined immunodeficiency HLA-matched (n = 41) and T-cell-depleted HLA-mismatched BMT (n = 46) resulted in 68% and 57% disease-free survival, respectively; after HLA-mismatched transplants, older age (greater than 6 months) and adenosine-deaminase deficiency resulted in poorer survival. Eight other lethal immunodeficiencies, including profound T-cell deficiencies, Wiskott-Aldrich syndrome, Kostmann syndrome, LFA-1/CR 3/p150,95 deficiency, and Chediak-Higashi syndrome as well as malignant osteopetrosis, have been successfully treated by BMT. In this group, survival with functional graft was 47% with HLA-matched and 29% with T-cell-depleted HLA-mismatched BMT. Engraftment failure was the major complication in this group. Poorer prognosis was associated with older patients, profound T-cell deficiencies, and the degree of HLA incompatibility.
2 patients with fast and 4 with medium varieties of Gaucher's syndrome were treated by displacement bone marrow transplantation to install a donor enzyme factory for life. Immunoprophylaxis was given to prevent host impairment of normal enzymes. 5 patients showed rapid and remarkable improvement and were leading fully active lives at 310-1207 days postgraft. Hypersplenism caused the death of 1 patient and a stormy time for another. Pre-transplant elective splenectomy hastened recovery.
The first case of successful bone marrow transplantation (BMT) in a patient with I-cell disease is reported. A 8-month-old girl with I-cell disease (N-acetylglucosaminylphosphotransferase deficiency) has had successful reconstitution with bone marrow from her HLA-MLC-matched brother who has heterozygous level of the transferase activity. The following biochemical and clinical improvements have occurred: the transferase in peripheral lymphocytes increased to donor's level, and lymphocytic alpha-neuraminidase, beta-galactosidase and alpha-mannosidase increased to normal levels. Plasma acid hydrolase activities, which had been 10 to 60 times higher in the patient than normal control levels, have slowly but steadily decreased from one month after the graft. Such decreases were observed in the activities of alpha-mannosidase, N-acetyl-beta-glucosaminidase, alpha-fucosidase, arylsulfatase A and acidic beta-galactosidase. There was also a marked decrease of vacuolated peripheral lymphocyte after the BMT. Three-months after the engraftment, hepatomegaly gradually decreased in size, corneal clouding has not progressed, and tight skin seems to have improved.
Allogenic bone marrow transplantation was carried out on a 3 year old girl with Niemann-Pick disease type B. Successful engraftment was achieved, and nine months after the procedure there was definite clearing of the sphingomyelin from the liver and pronounced clearing from the bone marrow. Any patient with Niemann-Pick disease type B complicated by early or severe hepatic impairment should be considered for bone marrow transplantation.
The experience of the Royal Children's Hospital in managing patients with mucopolysaccharidosis is discussed. All share the common feature of abnormal storage, within lysosomes, of partially degraded glycosaminoglycans, but different diseases within the group as a whole present different problems. The presentation, diagnosis and clinical outcome of 69 affected children are described.