IN VIVO ADA GENE DELIVERY FOR THE TREATMENT OF SCID

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Severe combined immune deficiency (SCID) represents the most extreme primary immune deficiency with a life-span of 1-2 years in most children without therapy due to overwhelming infections. Adenosine deaminase (ADA)-deficient SCID, which accounts for ~20% of human cases of SCID, is unique among the different genetic types of SCID in that it results from the absence of an enzyme (ADA). Although ADA is expressed in all tissues, the absence of ADA enzyme is most critical to the survival of lymphocytes and, in the absence of ADA, toxic metabolites accumulate in lymphocytes and causes severe metabolic derangements and cell death. Besides bone marrow transplantation that can be used to treat SCID, enzyme replacement therapy (ERT) with bovine polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) can be beneficial to patients with ADA-deficient SCID. However, PEG-ADA ERT only provides partial restoration of immune function and it requires ongoing bi-weekly intramuscular injections of the very expensive enzyme preparation. The objective of these studies is to assess vector pharmacokinetics, dosimetry, and biodistribution in infant monkeys as pre-clinical studies prior to testing in human infants. We will measure vector plasma clearance, vector biodistribution, and vector genome persistence, and measure in vivo ADA gene expression. These studies are essential to initiate considerations of translation of this approach to human ADA-deficient SCID pediatric patients.