Gene Therapy for ADA-Deficient SCID

Children'S Hospital Of Los Angeles, Los Angeles CA

Investigators

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Abstract

Principal Investigator/Program Director (Last, first, middle): Kohn, Donald B. Genetic deficiency of adenosine deaminase (ADA), an enzyme of purine metabolism, is a cause of approximately 20% of cases of severe combined immunodeficiency (SCID). ADA-deficient SCID as been approached by gene transfer into T lymphocytes and hematopoietic stem cells (HSC), but no significant clinical benefit has been realized by the subjects. The availability of effective enzyme replacement therapy (PEG- ADA) for ADA-deficient SCID complicates the design and interpretation of clinical gene transfer research studies. In a clinical trial we began in 1993, CD34+ cells from the umbilical cord blood of three ADA-deficient SClD neonates were transduced with a retroviral vector carrying a normal human ADA cDNA and transplanted into the infants, who were also treated with PEG-ADA. The frequency of engrafted transduced HSC was low (-1t10, 000), but there was a selective increase of the frequency of gene-containing T lymphocytes (-1/10) as PEG-ADA was withdrawn.. There was not detectable expression from the retroviral vector in resting peripheral blood T lymphocytes, but expression could be induced to readily detectable levels upon in vitro stimulation of the T lymphocytes. Possibly, there was expression by the vector in activated thymocytes, conferring selective survival of gene-containing T lymphocytes during thymopoiesis. There was not a parallel selective increase of the frequency of gene-containing B lymphocytes and NK cells, and the absolute numbers of B lymphocytes and NK cells fell when PEG-ADA was stopped for two months. A recent study of ADA gene transfer to bone marrow HSC in which subjects were given modest dosages of cytoreductive chemotherapy and in which PEG- ADA enzyme therapy was withheld, has shown initial evidence for immune reconstitution, although whether this is attributable to the chemotherapy, the absence of PEG-ADA or both is unclear. Thus, a number of questions regarding the optimal approach to gene therapy for ADA-deficient SCID remain. A murine model of ADA-deficient SCID which reflects many major aspects of the human immunodeficiency disease has been developed by ADA gene knock-out, rescue of perinatal mortality by placental expression of an ADA transgene, and prolongation of post-natal survival by administration of PEG-ADA. We will use this model to study aspects of gene transfer to guide the development of future clinical trials of gene transfer research by performing the following Specific Aims: 265 [unreadable] Principal Investigator/Program Director (Last, first, middle): DETAILED BUDGET FOR INITIAL BUDGET PERIOD DIRECT COSTS ONLY