Neurogenetic diseases cause tens of thousands of deaths in the United States each year, inflict immeasurable pain and suffering, and consume a substantial portion of scarce healthcare resources. A mouse counterpart for many of these diseases does not exist necessitating the creation and use of new mammalian models. Despite the significant challenges associated with the development of monkey models of neurogenetic diseases, the time is appropriate and the need is compelling. Accordingly, our long-term goal is to produce genetically modified Rhesus monkeys that will serve as models for human neurogenetic diseases. We will focus on three, early-onset, loss of function conditions: Kallmann's syndrome, Lesch-Nyhan's disease and Ataxia-Telangiectasia. We will attempt to establish the paradigm relatively quickly, an objective that can not be met with diseases that require decades to reveal themselves. Because Kallmann's syndrome and Lesch-Nyhan's disease are due to mutations in genes located on the X chromosome (KAL1 and HPRT, respectively), loss of function XY cell mutations require disruption of only one allele. Disruption of the two copies of the autosomal Ataxia Telangiectasia Mutated (ATM) gene, while more difficult, will establish the methods necessary for disrupting autosomal genes in vitro. Our working hypothesis is that gene targeting and somatic cell cloning technology can, in combination, provide the basis for generating a reliable supply of animals that accurately represent human disease. The objective of this application is to create the infrastructure necessary to genetically modify Rhesus monkey cells in culture and to use those cells as donors for nuclear transfer. The resultant viable embryos of the desired genotype can then be transferred into surrogate mothers. Genetically modified Rhesus macaques will result. Such animals should provide a resource for the study of human neurogenetic diseases and serve as pre-clinical models for new experimental treatments including gene and stem cell based therapies.
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