1. Clinical efficacy of gene-modified stem cells in adenosine deaminase–deficient immunodeficiency
- Author
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Sally Shupien, Linda M. Muul, Fabio Candotti, Berkley Brown, Pei Yu Fu, Rob Sokolic, Barbara Nowicki, Otto O. Yang, Aaron R. Cooper, Andrew M. Scharenberg, Christopher Silvin, David W. Gjertson, Alejandra Davila, Kit L. Shaw, Dayna Terrazas, Donald B. Kohn, Alan Ikeda, Beatriz Campo Fernandez, Radha G. Rishi, Neena Kapoor, Xiaoyan Wang, Denise Carbonaro, Suparna Mishra, Arumugam Balamurugan, G. Jayashree Jagadeesh, Satiro N. De Oliveira, Yeong Choi, Kenneth Cornetta, Suzanne Skoda-Smith, Michael S. Hershfield, Roshini S. Abraham, Sabine Geiger, David Buchbinder, Barbara C. Engel, Provaboti Barman, Theodore B. Moore, Kathey Mohan, E. Monika Smogorzewska, Elizabeth Garabedian, Allen Yu, Ken Purdy, John Tse, Greg M. Podsakoff, and Stacie M. Anderson
- Subjects
Male ,0301 basic medicine ,Oncology ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Adolescent ,Adenosine Deaminase ,Genetic enhancement ,medicine.medical_treatment ,Genetic Vectors ,CD34 ,Hematopoietic stem cell transplantation ,Gene Expression Regulation, Enzymologic ,03 medical and health sciences ,Agammaglobulinemia ,Transduction, Genetic ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Progenitor cell ,Autografts ,Child ,business.industry ,Hematopoietic Stem Cell Transplantation ,Infant ,nutritional and metabolic diseases ,Genetic Therapy ,General Medicine ,medicine.disease ,3. Good health ,Adenosine deaminase deficiency ,Transplantation ,Retroviridae ,surgical procedures, operative ,030104 developmental biology ,Child, Preschool ,Female ,Severe Combined Immunodeficiency ,Clinical Medicine ,Stem cell ,business ,Busulfan ,medicine.drug - Abstract
Background Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells is an alternative to enzyme replacement therapy (ERT) and allogeneic HSCT that has shown clinical benefit for adenosine deaminase-deficient (ADA-deficient) SCID when combined with reduced intensity conditioning (RIC) and ERT cessation. Clinical safety and therapeutic efficacy were evaluated in a phase II study. Methods Ten subjects with confirmed ADA-deficient SCID and no available matched sibling or family donor were enrolled between 2009 and 2012 and received transplantation with autologous hematopoietic CD34+ cells that were modified with the human ADA cDNA (MND-ADA) γ-retroviral vector after conditioning with busulfan (90 mg/m2) and ERT cessation. Subjects were followed from 33 to 84 months at the time of data analysis. Safety of the procedure was assessed by recording the number of adverse events. Efficacy was assessed by measuring engraftment of gene-modified hematopoietic stem/progenitor cells, ADA gene expression, and immune reconstitution. Results With the exception of the oldest subject (15 years old at enrollment), all subjects remained off ERT with normalized peripheral blood mononuclear cell (PBMC) ADA activity, improved lymphocyte numbers, and normal proliferative responses to mitogens. Three of nine subjects were able to discontinue intravenous immunoglobulin replacement therapy. The MND-ADA vector was persistently detected in PBMCs (vector copy number [VCN] = 0.1-2.6) and granulocytes (VCN = 0.01-0.3) through the most recent visits at the time of this writing. No patient has developed a leukoproliferative disorder or other vector-related clinical complication since transplant. Conclusion These results demonstrate clinical therapeutic efficacy from gene therapy for ADA-deficient SCID, with an excellent clinical safety profile. Trial registration ClinicalTrials.gov NCT00794508. Funding Food and Drug Administration Office of Orphan Product Development award, RO1 FD003005; NHLBI awards, PO1 HL73104 and Z01 HG000122; UCLA Clinical and Translational Science Institute awards, UL1RR033176 and UL1TR000124.
- Published
- 2017
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