FELINE MODEL OF NIEMANN-PICK TYPE C

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Niemann-Pick diseases type C (NPC) is an autosomal recessive lysosomal storage disorder with a variety of clinical features including neonatal jaundice, seizures, delayed mental and motor development, and premature death. Patients with NPC store a variety of lipids in their liver, including cholesterol, glucosylceramide, lactosylceramide, and phospholipids including sphingomyelin. An abnormal pattern of gangliosides is also present in the brain. Although these patients were previously thought to have a defect in cholesterol metabolism, it is not apparent that these changes in lipid composition are due to a defect in sphingomyelin metabolism, it is now apparent that these changes in lipid composition are due to defect in cholesterol metabolism, the molecular basis of which is unknown. Cultured skin fibroblasts show a decreased ability to esterify exogenous cholesterol presented to cholesterol- depleted cells as low density lipoprotein. This is a proposal to establish a colony of cats with a genetic disease clinically and biochemically identical to NPC in man. A family of domestic cats has recently been identified in which kittens have neurologic abnormalities died at less than one year of age. Examination of the lipids in liver and gangliosides in brain tissue of these kittens show a pattern identical to that found in tissues from human patients with NPC. Cultured skin fibroblasts are found to have near complete inability to esterify exogenous cholesterol. We have secured five cats from the original family (the mother, 3 female siblings and 1 male sibling). Breeding trials have established that a least 3 of these cats are carriers of NPC, including the male. We have produced 10 NPC affected kittens. We propose to expand the colony to make affected cats available to other research groups interested in defects of cholesterol metabolism, disorders of lipid metabolism, lysosomal storage diseases, disorders of neuronal function and to facilitate investigations of modes of therapy for these diseases. The specific aims of this proposal are to 1) establish a colony of cats with the biochemical and morphologic equivalent of human NPC, 2) provide these cats to researchers interested in this genetic disease and defects in cholesterol metabolism, 3) to determine the effectiveness of bone marrow transplantation as therapy for NPC affected cats, and 5) to determine the effectiveness of cholesterol lowering drugs as therapy for NPC affected cats. Six heterozygotes will be maintained to increase the size of the breeding colony, and to increase production of affected kittens. Five affected kittens will be maintained as non=treated controls for the therapy studies. Three affected kittens will receive bone marrow transplants at 4 weeks of age. Five affected kittens will be fed very low cholesterol diet beginning at 4 weeks of age. Nine affected kittens will be placed in groups of 3 and given 3 different cholesterol lowering drugs. All treated cats will be compared biochemically, clinically, and morphologically to their nontreated controls.