ANIMAL MODEL FOR GENE THERAPY OF INHERITED DISORDERS

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The objectives of this grant are to maintain and propagate a colony of rhesus monkeys that are carriers of globoid cell leukodystrophy (GLD) and to characterize GLD as it occurs in homozygous affected individuals. The long-term goal of this project is to develop a nonhuman primate animal model for gene therapy of inborn errors of metabolism. This colony of rhesus monkeys is the only colony of nonhuman primates in the world in which an inherited lysosomal disorder has been recognized, propagated, and is available for study. No other nonhuman primate model is available in which to test the actual clinical effectiveness of various therapeutic interventions in animals with a genetic disease. There are 21 carrier monkeys in the colony. They will be socially housed and bred naturally or artificially. Fetal growth will be monitored by ultrasound. Before or after birth, infants will be diagnosed by biochemistry and polymerase chain reaction as homozygous normal, heterozygous carrier, or homozygous affected. Infants will be characterized clinically, behaviorally, neurophysiologically, pathologically, and by neuroimaging. These data will be used in future applications as a baseline against which to compare the effects of therapeutic interventions, particularly gene therapy. We believe the specific aims of this proposal span the interests of several NIH institutes. These include the NCRR (animal models, biotechnology), the NINDS (neurogenetic disorders of infancy and childhood), the NIDDKD (development of somatic gene therapy approaches for inborn metabolic diseases), and the NICHHD (therapeutics during pregnancy, developmental abnormalities). The ability to study the in vivo efficacy and safety of gene therapy protocols in a nonhuman primate animal model with a genetic disease will be a powerful tool for advancing the prospects of genetic medicine in humans.