Deficiency of adenosine deaminase (ADA) is responsible for 20% of human severe combined immune deficiency (SCID). Current therapies for ADA-deficient SCID have clinical benefits, but each approach has limitations. Thus, development of novel therapeutic approaches are important for this form of SCID and these advances may have therapeutic applications for other primary immune deficiencies, blood cell diseases and metabolic disorders. The unique pathophysiology of ADA-deficient SCID, with the potential for trans-correction of the immune deficiency by ectopic expression of ADA, may allow a novel therapy to be developed. We have determined in a murine ADA gene knock-out mouse model that a single I.V. administration of a lentiviral vector carrying a normal human ADA cDNA leads to systemic ADA gene delivery and ADA enzyme expression that restores immunity and significantly prolongs survival. The central hypothesis of this proposal is that: In vivo systemic delivery of a normal ADA gene will be clinically beneficial for correcting the biochemical and immunologic abnormalities of ADA-deficient SCID, providing efficacy similar to or greater than that of exogenous enzyme replacement therapy, but as a single treatment, rather than as a chronic regimen. To assess this hypothesis, we will 1. optimize in vivo gene delivery by IV vector administration in ADA gene knock-out mice, 2. evaluate the mechanisms of the effect from in vivo ADA gene delivery, and 3. define large animal vector dosimetry, pharmacokinetics, bio-distribution and toxicology as pre-clinical studies. The overall goals of this Proposal are to optimize the efficacy of systemic ADA gene delivery, to gain better understanding of the mechanisms of the therapeutic effects and to perform initial pre- clinical studies in a large animal model. Relevance to public health: Primary immune deficiency diseases are serious, life-threatening disorders with patients often developing severe, life-threatening infections in the first years of life. Current therapies for these diseases have significant efficacy, but remain sub-optimal. Therefore, it is imperative to continue to develop new and improved methods to treat primary immune deficiency diseases and that is the primary goal of this project have significant efficacy, but remain sub-optimal.
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