Allogeneic hematopoietic stem cel transplant for sickle cell disease: The time is now

Molecular and Clinical Hematology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Blood (Impact Factor: 10.45). 05/2011; 118(5):1197-207. DOI: 10.1182/blood-2011-01-332510
Source: PubMed


Although sickle cell disease (SCD) has a variable clinical course, many patients develop end-organ complications that are associated with significant morbidity and early mortality. Myeloablative allogeneic HSCT (allo-HSCT) is curative but has been historically performed only in children younger than 16 years of age. Modest modifications in the conditioning regimen and supportive care have improved outcome such that the majority of children with a suitable HLA-matched sibling donor can expect a cure from this approach. However, adult patients have been excluded from myeloablative allo-HSCT because of anticipated excess toxicity resulting from accumulated disease burden. Efforts to use nonmyeloablative transplantation strategies in adults logically followed but were initially met with largely disappointing results. Recent results, however, indicate that nonmyeloablative allo-HSCT in adult patients with SCD allows for stable mixed hematopoietic chimerism with associated full-donor erythroid engraftment and normalization of blood counts, and persistence in some without continued immunosuppression suggests immunologic tolerance. The attainment of tolerance should allow extension of these potentially curative approaches to alternative donor sources. Efforts to build on these experiences should increase the use of allo-HSCT in patients with SCD while minimizing morbidity and mortality.

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    • "Recently, transplantation trials in humans and numerous animal studies have shown that complete correction or replacement of the hematopoietic stem cell pool or correction of the βS point mutation itself are not required to provide therapeutic benefits [18-20]. Given these encouraging trials and the natural history of sickle cell trait, we sought to introduce a competing anti-sickling globin gene to HSCs to test for potential phenotypic correction. "
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    ABSTRACT: The ultimate goal of gene therapy for sickle cell anemia (SCA) is an improved phenotype for the patient. In this study, we utilized bone marrow from a sickle cell patient as a model of disease in an in vitro setting for the hyperactive Sleeping Beauty transposon gene therapy system. We demonstrated that mature sickle red blood cells containing hemoglobin-S and sickling in response to metabisulfite can be generated in vitro from SCA bone marrow. These cells showed the characteristic morphology and kinetics of hemoglobin-S polymerization, which we quantified using video microscopy and imaging cytometry. Using video assessment, we showed that delivery of an IHK-β(T87Q) antisickling globin gene by Sleeping Beauty via nucleofection improves metrics of sickling, decreasing percent sickled from 53.2 ± 2.2% to 43.9 ± 2.0%, increasing the median time to sickling from 8.5 to 9.6 min and decreasing the maximum rate of sickling from 2.3 x 10(-3) sickling cells/total cells/sec in controls to 1.26 x 10(-3) sickling cells/total cells/sec in the IHK-β(T87Q)-globin group (p < 0.001). Using imaging cytometry, the percentage of elongated sickled cells decreased from 34.8 ± 4.5% to 29.5 ± 3.0% in control versus treated (p < 0.05). These results support the potential use of Sleeping Beauty as a clinical gene therapy vector and provide a useful tool for studying sickle red blood cells in vitro.
    PLoS ONE 11/2013; 8(11):e80403. DOI:10.1371/journal.pone.0080403 · 3.23 Impact Factor
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    • "For the best chance at transplant success, a HLA-matched family donor is needed, but is only available in 14–18% of children with SCA. The major risks of transplant include infection, graft-versus-host disease (GVHD), failure to engraft, and death(Hsieh, et al 2011). Early concerns about central nervous system (CNS) complications, such as seizures, associated with transplantation appear to have been ameliorated by aggressive treatment with platelets and anti-convulsant medication. "
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    ABSTRACT: This review will focus on the strengths and limitations associated with the current standard of care for primary prevention of ischaemic strokes in children with sickle cell anaemia (SCA) - transcranial Doppler ultrasound (TCD) screening followed by regular blood transfusion therapy when TCD measurement is above a threshold defined by a randomized clinical trial (RCT). The theoretical basis for potential alternative strategies for primary prevention of neurological injury in SCA is also discussed. These strategies will include, but will not be limited to: immunizations to prevent bacterial infections, particularly in low income countries; management of elevated blood pressure; and targeted strategies to increase baseline haemoglobin levels with therapies such as hyroxycarbamide or potentially definitive haematopoietic stem cell transplant.
    British Journal of Haematology 01/2012; 157(1). DOI:10.1111/j.1365-2141.2011.09005.x · 4.71 Impact Factor
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    ABSTRACT: Progression of vasculopathy associated with moyamoya syndrome is extremely variable. The authors review their experience in patients with unilateral moyamoya syndrome to identify factors predictive of contralateral clinical and imaging-documented disease progression. The authors reviewed the clinical and imaging records of all patients with moyamoya syndrome and unilateral disease who underwent cerebral revascularization surgery between January 1985 and June 2006 by using a standardized surgical procedure, pial synangiosis. Of 235 surgically treated patients with moyamoya syndrome, 33 (14%) presented with unilateral disease (4 adults and 29 children). There were 16 female and 17 male patients, with an average age of 10.4 years (26.8 years for adults and 8.1 years for children; range 1.5-39 years). Twenty patients presented with left-sided disease and 13 with right-sided disease. The average follow-up after surgery was 5.3 years (3.1 years for adults and 5.6 years for children; range 1-16 years). During this period, 10 (30%) of 33 patients progressed to bilateral disease. The mean time until disease progression was 2.2 years (range 0.5-8.5 years). Factors associated with progression in this series included contralateral abnormalities on initial angiography, previous history of congenital cardiac anomaly, cranial irradiation, Asian ancestry, and familial moyamoya syndrome. Young age at diagnosis was associated with a more rapid rate of progression (age < 7 years, 0.9 years to progression and age >or= 7 years, 3.1 years to progression). Of patients with unilateral moyamoya syndrome, 30% will have progression of arteriopathy during long-term follow-up. In this series, the average time of progression from unilateral to bilateral angiographic disease was 2.2 years. Several factors, including contralateral abnormalities on initial imaging, congenital cardiac anomaly, previous cranial irradiation, Asian ancestry, and familial moyamoya syndrome, were associated with an increased risk of progression. Patients with known unilateral angiographic disease should undergo continued monitoring by using MR imaging and MR angiography at regular intervals. Treatment with pial synangiosis is safe and confers durable protection against stroke in patients with both bilateral and unilateral moyamoya syndrome.
    Neurosurgical FOCUS 02/2008; 24(2):E17. DOI:10.3171/FOC/2008/24/2/E17 · 2.11 Impact Factor
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