Cord-Blood Transplants from Unrelated Donors in Patients with Hurler's Syndrome

Pediatric Stem Cell Transplant Program, Duke University Medical Center, Durham, NC 27710, USA.
New England Journal of Medicine (Impact Factor: 55.87). 06/2004; 350(19):1960-9. DOI: 10.1056/NEJMoa032613
Source: PubMed


Hurler's syndrome (the most severe form of mucopolysaccharidosis type I) causes progressive deterioration of the central nervous system and death in childhood. Allogeneic bone marrow transplantation before the age of two years halts disease progression and prolongs life, but many children lack a bone marrow donor. We investigated the feasibility of using cord-blood transplants from unrelated donors and a myeloablative preparative regimen that did not involve total-body irradiation in young children with Hurler's syndrome.
Between December 1995 and October 2002, 20 consecutive children with Hurler's syndrome received busulfan, cyclophosphamide, and antithymocyte globulin before receiving cord-blood transplants from unrelated donors. The children were subsequently evaluated for engraftment, adverse effects, and effects on disease symptoms.
Cord-blood donors had normal alpha-L-iduronidase activity (mean number of cells, 10.53x10(7) per kilogram of body weight) and were discordant for up to three of six HLA markers. Neutrophil engraftment occurred a median of 24 days after transplantation. Five patients had grade II or grade III acute graft-versus-host disease; none had extensive chronic graft-versus-host disease. Seventeen of the 20 children were alive a median of 905 days after transplantation, with complete donor chimerism and normal peripheral-blood alpha-L-iduronidase activity (event-free survival rate, 85 percent). Transplantation improved neurocognitive performance and decreased somatic features of Hurler's syndrome.
Cord blood from unrelated donors appears to be an excellent source of stem cells for transplantation in patients with Hurler's syndrome. Sustained engraftment can be achieved without total-body irradiation. Cord-blood transplantation favorably altered the natural history of Hurler's syndrome and thus may be important to consider in young children with this form of the disease.

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    • "T-cell depletion and reduced-intensity conditioning were identified as risk factors for graft failure, whereas patients receiving cord blood had a greater likelihood of achieving sustained engraftment associated with normal enzyme levels. In 2004, unrelated UCBT was reported in 20 patients with Hurler syndrome [18] with an overall EFS rate of 85% and a probability of moderate to severe acute GVHD of 25%; all surviving patients demonstrated complete engraftment and immune reconstitution and normal peripheral-blood α-L-iduronidase activity. Two large studies comprising 93 and 45 patients with MPS1-H [6] [19], respectively, confirmed these results. "
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    ABSTRACT: For patients with mucopolysaccharidosis type IH (MPS1-H; Hurler syndrome), early allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice. One boy and one girl aged 20.5 and 22 months, respectively, with MPS1-H received a conditioning regimen consisting of thiotepa, fludarabine, treosulfan, and ATG. Grafts were peripheral blood stem cells from unrelated donors (10/12 and 11/11 matched), that were manipulated by CD3/CD19 depletion and contained 20.3 and 28.2 × 106 CD34+ cells/kg body weight, respectively. Both patients achieved stable hematopoietic engraftment and stable donor chimerism. Neither acute or chronic graft-versus-host disease (GVHD) nor other severe transplant-related complications occurred. At a follow-up of 48 and 37 months, both patients are alive and well with normal levels of α-L-iduronidase and have made major neurodevelopmental progress. Treosulfan-based conditioning offers the advantage of reduced toxicity; the use of unrelated CD3/CD19-depleted peripheral stem cell grafts allows transfusion of high CD34+ cell numbers together with a “tailored” number of CD3+ cells as well as engraftment facilitating cells in order to achieve rapid hematopoietic engraftment while reducing the risk of graft rejection and GVHD. This regimen might be an additional option when unrelated donor HSCT is considered for a patient with MPS1-H.
    Pediatric Hematology and Oncology 08/2014; 31(8). DOI:10.3109/08880018.2014.939794 · 1.10 Impact Factor
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    • "Mucopolysaccharidosis (MPS) are a family of inherited disorders caused by deficiency of lysosomal enzymes needed to degrade glycosaminoglycans (GAGs). Since the first transplantations performed 30 years ago [107], major beneficial results have been obtained in patients with Hurler syndrome [79, 147, 150]. From these impressive results, it was expected that all MPS could be treated by HCT. "
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    ABSTRACT: Microglia have long been the focus of much attention due to their strong proliferative response (microgliosis) to essentially any kind of damage to the CNS. More recently, we reached the realization that these cells play specific roles in determining progression and outcomes of essentially all CNS disease. Thus, microglia has ceased to be viewed as an accessory to underlying pathologies and has now taken center stage as a therapeutic target. Here, we review how our understanding of microglia's involvement in promoting or limiting the pathogenesis of diseases such as amyotrophic lateral sclerosis, Alzheimer's disease, Huntington's disease, multiple sclerosis, X-linked adrenoleukodystrophy (X-ALD) and lysosomal storage diseases (LSD) has changed over time. While strategies to suppress the deleterious and promote the virtuous functions of microglia will undoubtedly be forthcoming, replacement of these cells has already proven its usefulness in a clinical setting. Over the past few years, we have reached the realization that microglia have a developmental origin that is distinct from that of bone marrow-derived myelomonocytic cells. Nevertheless, microglia can be replaced, in specific situations, by the progeny of hematopoietic stem cells (HSCs), pointing to a strategy to engineer the CNS environment through the transplantation of modified HSCs. Thus, microglia replacement has been successfully exploited to deliver therapeutics to the CNS in human diseases such as X-ALD and LSD. With this outlook in mind, we will discuss the evidence existing so far for microglial involvement in the pathogenesis and the therapy of specific CNS disease.
    Acta Neuropathologica 08/2014; 128(3). DOI:10.1007/s00401-014-1330-y · 10.76 Impact Factor
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    • "As HSCT is increasingly successful due to improved conditioning regimens and different stem cell sources, over 80% of patients now remain alive and engrafted with a significantly improved life expectancy [24,25]. However, there is a paucity of data regarding which successfully transplanted patients will develop hip dysplasia, which patients will develop symptoms of hip dysplasia, such as pain and impaired locomotion, and when surgical intervention is needed in patients with hip dysplasia. "
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    Orphanet Journal of Rare Diseases 10/2013; 8(1):155. DOI:10.1186/1750-1172-8-155 · 3.36 Impact Factor
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