FELINE MODEL OF NIEMANN-PICK TYPE C

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Niemann-Pick disease type C (NPC) is an autosomal recessive lysosomal storage disorder: clinical features include 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 present in the brain. NPC was previously thought to be due to a defect in sphingomyelin metabolism; it is now know that lipid storage results from a defect in cholesterol trafficking out of the lysosome and Golgi. This is a proposal to maintain and continue to characterize an excellent feline model of NPC, and the only large animal model available. Features common to this feline lipid storage disorder and human NPC include clinical neurological signs, mode of inheritance, hepatomegaly, neurovisceral storage as evidenced by light and electron microscopy, and biochemical analysis of storage (unesterified cholesterol, sphingomyelin, glycolipids, and gangliosides). Impaired ability of cultured skin fibroblasts to esterify exogenous cholesterol with perinuclear accumulation of unesterified cholesterol demonstrated by filipin staining is identical to the human disease. We have produced 26 NPC affected kittens in the last 6 years. 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. We also propose to continue to characterize this disorder. The specific aims of this proposal are to l) maintain a colony of NPC cats with a disorder identical to human NPC, and offer these cats and tissues to other investigators. 2) continue to biochemically and morphologically characterize feline NPC at various ages, including neonatally, 3) continue to evaluate effectiveness of bone marrow transplantation as therapy , 4) determine the effectiveness of low cholesterol diet with cholesterol lowering drugs as therapy, and 5) identify the gene which is responsible for feline NPC. Approximately 12 heterozygotes will be maintained to increase the size of the breeding colony, and to increase production of affected kittens. Affected kittens will be continue to he evaluated as non treated controls. Two affected kittens will receive bone marrow transplants at l week of age. Four affected kittens will be fed very low cholesterol diet and cholesterol lowering drugs beginning at 1-2 weeks of age. Fetal cats will be removed from the uterus at varying ages and evaluated biochemically (lipid and ganglioside analyses) and morphologically by light and electron microscopy. We will continue to collect DNA from all kittens to improve chances of finding the homologous gene for NPC. The continued existence of this colony will provide a critically needed biological tool to examine future therapeutic trials involving both gene and protein replacement therapies.