NONHUMAN PRIMATE MODEL FOR KRABBE'S DISEASE

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. The long-term goal of this proposal is to expand and study our colony of nonhuman primates affected with Globoid Cell Leukodystrophy (Krabbe's disease). Nonhuman primates are a critical step, before human trials, for evaluating the effectiveness and safety of novel therapies. This colony of rhesus monkeys represents the only colony of nonhuman primates in the world in which an inherited lysosomal disorder has been recognized, propagated, and is available for study. In order for this unique animal model to be useful to the scientific community, we must be able to reliably produce a significant number of affected offspring, which was the original goal of this R24. The generation of large numbers of affected animals requires long-term support to expand this colony and to develop new methods with which to produce both carrier and affected offspring. The primary focus of the proposed renewal of this R24 grant is aimed at markedly improving the efficiency of producing macaques affected with Globoid Cell Leukodystrophy (GLD) through a stringent natural breeding program. As a minor component of these studies, we propose to utilize several proven assisted reproductive technologies (ART) techniques for the production of rhesus macaque embryos that are homozygous for globoid cell leukodystrophy. The primary aims of this portion of our research are to i) produce embryos by in vitro fertilization using oocytes and semen from Krabbe's carrier animals; ii) to perform preimplantation genetic diagnosis (PGD) to establish the Krabbe genotype of these embryos and; iii) to "bank" these embryos by cryopreservation for possible use in the future. Secondly, we will continue to analyze disease pathogenesis and generate a database with the affected animals through molecular, biochemical, clinical, behavioral, and pathologic analyses. The proposed studies are critical for us to develop an extensive baseline of knowledge of disease progression in the nonhuman primate model, which, in the end, will be essential for the design and implementation of therapeutic interventions in the future. Lastly, one of the primary limitations of the GLD nonhuman primate model to date is unavailability of large numbers of affected animals. The limited number of GLD-affected animals has severely hampered our understanding of this disease model, but more importantly, the development and testing of therapeutic protocols. As an effective alternative to whole animal studies, we have initiated a cell and tissue banking program for the GLD animals. The primary goal for this program is to make viable cells (peripheral blood and bone marrow mononuclear cells, mesenchymal stem cells, and skin fibroblasts) and tissue samples (primary organ systems) available to investigators for their research.