99 Autologous Transplant/Gene Therapy for Adenosine Deaminase-Deficient Severe Combined Immune Deficiency

Track: Pediatric BMT Program
Thursday, February 12, 2015, 5:45 PM-7:15 PM
Grand Hall AB (Manchester Grand Hyatt)
Donald B. Kohn , Microbiology, Immunology & Molecular Genetics and Pediatrics, University of California, Los Angeles, Los Angeles, CA
Kit L Shaw , Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA
Robert Sokolic, MD , National Human Genome Research Institute, Bethesda, MD
Denise A Carbonaro , Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA
Alejandar Davila , Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA
Provaboti Barman , Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA
Elizabeth Garabedian , National Genome Research Institute, NIH, Bethesda, MD
Christopher Silvin , National Genome Research Institute, NIH, Bethesda, MD
Satiro De Oliveira, MD , Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
Ami J Shah, MD , Pediatrics (Hematology/Oncology), University of California, Los Angeles, Los Angeles, CA
Theodore B Moore, MD , Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA
Michael Hershfield , Biochemistry and Medicine, Duke University School of Medicine, Durham, NC
Adrian Thrasher , Institute of Child Health, University College LOndon, London, United Kingdom
H. Robert Gaspar , Institute of Child Health, University College London, London, United Kingdom
Fabio Candotti , NHGRI, NIH, Bethesda, MD
Audio File Recorded Presentation
Autologous hematopoietic stem cell transplantation (HSCT) of gene-modified cells (gene therapy) has shown clinical benefit for ADA-SCID when combined with non-myeloablative conditioning and enzyme replacement therapy (ERT) cessation.  In a Phase II study (2009-2012) closed to enrollment (NCT00794508), patients received autologous CD34+ cells modified with the MND-ADA g-retroviral vector after conditioning with busulfan (4 mg/kg) and ERT cessation (n=10).  Patients were treated between 3 months and 15 years of age (median=11.5 months) and follow-up ranges from 22-64 months.  With the exception of the oldest patient (at 15y), all others remain off ERT with normalized PBMC ADA activity.  All nine remaining off ERT show normal proliferative responses to mitogens and three of nine were able to discontinue IVIg. MND-ADA is detected in PBMC (0.1-2.6 VCN) and in granulocytes (0.01-0.3 VCN) at most recent visit.  A new Phase I/II trial was opened in May 2013 (NCT01852071) in which subjects have received autologous CD34+ cells modified with a self-inactivating lentiviral vector (EFS-ADA) after conditioning with busulfan (4 mg/kg) with ERT cessation at 30 days post-transplant (n=6). Eight subjects have been enrolled at 4-42 months old and the six who are past 30 days remain off ERT.  The patients with the longest follow-up have normal or higher PBMC ADA activity and good immune reconstitution.  Monitoring for insertional oncogenesis is on-going in both studies and has not detected any monoclonal proliferative events. These results demonstrate the efficacy and safety of autologous transplant/gene therapy for ADA SCID.
Disclosures:
Nothing To Disclose
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