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Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction

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Abstract
Genetic defects in the purine salvage enzyme adenosine deaminase (ADA) lead to severe combined immunodeficiency (SCID) with profound depletion of T, B, and natural killer cell lineages. Human leukocyte antigen-matched allogeneic hematopoietic stem cell transplantation (HSCT) offers a successful treatment option. However, individuals who lack a matched donor must receive mismatched transplants, which are associated with considerable morbidity and mortality. Enzyme replacement therapy (ERT) for ADA-SCID is available, but the associated suboptimal correction of immunological defects leaves patients susceptible to infection. Here, six children were treated with autologous CD34-positive hematopoietic bone marrow stem and progenitor cells transduced with a conventional gammaretroviral vector encoding the human ADA gene. All patients stopped ERT and received mild chemotherapy before infusion of gene-modified cells. All patients survived, with a median follow-up of 43 months (range, 24 to 84 months). Four of the six patients recovered immune function as a result of engraftment of gene-corrected cells. In two patients, treatment failed because of disease-specific and technical reasons: Both restarted ERT and remain well. Of the four reconstituted patients, three remained off enzyme replacement. Moreover, three of these four patients discontinued immunoglobulin replacement, and all showed effective metabolic detoxification. All patients remained free of infection, and two cleared problematic persistent cytomegalovirus infection. There were no adverse leukemic side effects. Thus, gene therapy for ADA-SCID is safe, with effective immunological and metabolic correction, and may offer a viable alternative to conventional unrelated donor HSCT.
Keywords
ENZYME REPLACEMENT, BONE-MARROW, GAMMARETROVIRAL VECTORS, IMMUNE RECONSTITUTION, SCID PATIENTS, ADA, TRANSPLANTATION, POPULATION, ACTIVATION, APOPTOSIS

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Chicago
Gaspar, H Bobby, Samantha Cooray, Kimberley C Gilmour, Kathryn L Parsley, Fang Zhang, Stuart Adams, Emma Bjorkegren, et al. 2011. “Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase-deficient Severe Combined Immunodeficiency Leads to Long-term Immunological Recovery and Metabolic Correction.” Science Translational Medicine 3 (97).
APA
Gaspar, H Bobby, Cooray, S., Gilmour, K. C., Parsley, K. L., Zhang, F., Adams, S., Bjorkegren, E., et al. (2011). Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. SCIENCE TRANSLATIONAL MEDICINE, 3(97).
Vancouver
1.
Gaspar HB, Cooray S, Gilmour KC, Parsley KL, Zhang F, Adams S, et al. Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction. SCIENCE TRANSLATIONAL MEDICINE. 2011;3(97).
MLA
Gaspar, H Bobby, Samantha Cooray, Kimberley C Gilmour, et al. “Hematopoietic Stem Cell Gene Therapy for Adenosine Deaminase-deficient Severe Combined Immunodeficiency Leads to Long-term Immunological Recovery and Metabolic Correction.” SCIENCE TRANSLATIONAL MEDICINE 3.97 (2011): n. pag. Print.
@article{8548576,
  abstract     = {Genetic defects in the purine salvage enzyme adenosine deaminase (ADA) lead to severe combined immunodeficiency (SCID) with profound depletion of T, B, and natural killer cell lineages. Human leukocyte antigen-matched allogeneic hematopoietic stem cell transplantation (HSCT) offers a successful treatment option. However, individuals who lack a matched donor must receive mismatched transplants, which are associated with considerable morbidity and mortality. Enzyme replacement therapy (ERT) for ADA-SCID is available, but the associated suboptimal correction of immunological defects leaves patients susceptible to infection. Here, six children were treated with autologous CD34-positive hematopoietic bone marrow stem and progenitor cells transduced with a conventional gammaretroviral vector encoding the human ADA gene. All patients stopped ERT and received mild chemotherapy before infusion of gene-modified cells. All patients survived, with a median follow-up of 43 months (range, 24 to 84 months). Four of the six patients recovered immune function as a result of engraftment of gene-corrected cells. In two patients, treatment failed because of disease-specific and technical reasons: Both restarted ERT and remain well. Of the four reconstituted patients, three remained off enzyme replacement. Moreover, three of these four patients discontinued immunoglobulin replacement, and all showed effective metabolic detoxification. All patients remained free of infection, and two cleared problematic persistent cytomegalovirus infection. There were no adverse leukemic side effects. Thus, gene therapy for ADA-SCID is safe, with effective immunological and metabolic correction, and may offer a viable alternative to conventional unrelated donor HSCT.},
  articleno    = {97ra80},
  author       = {Gaspar, H Bobby and Cooray, Samantha and Gilmour, Kimberley C and Parsley, Kathryn L and Zhang, Fang and Adams, Stuart and Bjorkegren, Emma and Bayford, Jinhua and Brown, Lucinda and Davies, E Graham and Veys, Paul and Fairbanks, Lynette and Bordon Cueto De Braem, Maria and Petropoulou, Theoni and Kinnon, Christine and Thrasher, Adrian J},
  issn         = {1946-6234},
  journal      = {SCIENCE TRANSLATIONAL MEDICINE},
  keywords     = {ENZYME REPLACEMENT,BONE-MARROW,GAMMARETROVIRAL VECTORS,IMMUNE RECONSTITUTION,SCID PATIENTS,ADA,TRANSPLANTATION,POPULATION,ACTIVATION,APOPTOSIS},
  language     = {eng},
  number       = {97},
  pages        = {9},
  title        = {Hematopoietic stem cell gene therapy for adenosine deaminase-deficient severe combined immunodeficiency leads to long-term immunological recovery and metabolic correction},
  url          = {http://dx.doi.org/10.1126/scitranslmed.3002716},
  volume       = {3},
  year         = {2011},
}

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