![]() ![]() 2Division of Pediatric Hematology/Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.1Division of Pediatric Allergy and Immunology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.(Funded by the National Institutes of Health and others numbers, NCT01852071, NCT02999984, and NCT01380990.).Ĭopyright © 2021 Massachusetts Medical Society. Treatment of ADA-SCID with ex vivo lentiviral HSPC gene therapy resulted in high overall and event-free survival with sustained ADA expression, metabolic correction, and functional immune reconstitution. No evidence of monoclonal expansion, leukoproliferative complications, or emergence of replication-competent lentivirus was noted, and no events of autoimmunity or graft-versus-host disease occurred. study discontinuing immunoglobulin-replacement therapy by 24 months and 36 months, respectively. Immune reconstitution was robust, with 90% of the patients in the U.S. Patients had sustained metabolic detoxification and normalization of ADA activity levels. studies and in 19 of 20 patients in the U.K. Engraftment of genetically modified HSPCs persisted in 29 of 30 patients in the U.S. study) at 12 months 97% and 95%, respectively, at 24 months and 95% (U.K. Event-free survival (in the absence of reinitiation of enzyme-replacement therapy or rescue allogeneic hematopoietic stem-cell transplantation) was 97% (U.S. Overall survival was 100% in all studies up to 24 and 36 months. study (in which a fresh formulation was used) at 36 months of follow-up. studies (in which fresh and cryopreserved formulations were used) at 24 months of follow-up were analyzed alongside data from the U.K. We treated 50 patients with ADA-SCID (30 in the United States and 20 in the United Kingdom) with an investigational gene therapy composed of autologous CD34+ hematopoietic stem and progenitor cells (HSPCs) transduced ex vivo with a self-inactivating lentiviral vector encoding human ADA. Severe combined immunodeficiency due to adenosine deaminase (ADA) deficiency (ADA-SCID) is a rare and life-threatening primary immunodeficiency. Ikeda) Cincinnati Children's Hospital Medical Center, Cincinnati (L.R.) Indiana University School of Medicine, Indianapolis (K.C.) Duke University, Durham, NC (R.P., R.H.B., M.H.) Division of Immunology and Allergy, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland (F.C.) and GeneWerk (M.Z., R.H., I.L., M.S.) and the German Cancer Research Center and the National Center for Tumor Diseases (M.Z., M.S.) - all in Heidelberg, Germany. Snell, D.L.-R., K.F.B., K.C.G., C.R., N.I., S.A., H.R., C.U., A.J.T., H.B.G.), and Orchard Therapeutics (Europe) (D.A.C.-S., S.A., F.L., M.K., A.S., H.B.G.) - all in London the National Institute of Allergy and Infectious Diseases (H.L.M.) and the National Human Genome Research Institute (E.G., R.S., F.C.), National Institutes of Health, Bethesda, MD Cure 4 The Kids Foundation, Las Vegas (A. Icreverzi, P.B., B.C.F., R.P.H., M.C., A.Y., K.M.C., C.E.C., R.Z.), Pediatrics (D.B.K., T.B.M., S.D.O., S.S.), and Pathology and Laboratory Medicine (G.M.C.) and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (D.B.K., G.M.C.), University of California, Los Angeles (UCLA), and the Department of Pharmaceutical Services, Ronald Reagan UCLA Medical Center (J.T.), Los Angeles, and Stanford School of Medicine, Palo Alto (A.J.S.) - all in California University College London Great Ormond Street Institute of Child Health and Great Ormond Street Hospital for Children NHS Foundation Trust (C.B., J.X.-B., V.T., K. 1 From the Departments of Microbiology, Immunology, and Molecular Genetics (D.B.K., K.L.S., D.A.C.-S., D.T., A.D., A. ![]()
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