Niemann-Pick type C (NP-C) disease is a fatal, autosomal recessive, childhood-on set neurodegenerative disorder for which there is no treatment. It is a lysosomal lipid storage disease characterized by defective trafficking of intracellular cholesterol, and lysosomal accumulation of unesterified cholesterol, gangliosides, and other lipids. Neurosteroids, synthesized from cholesterol in the nervous system, affect growth and differentiation of neurons. Our recently published data show that post-embryonic neurosteroid synthesis is altered in a time- and region- specific fashion in the BALB/c NP-C mouse, and that neurons and glia expressing steroidogenic enzymes are lost in the NP-C mouse. In particular, the synthesis of the GABA-ergic neurosteroid allopregnanolone (ALLO) is substantially diminished at birth when the rodent brain is still undergoing maturation, and decreases further over time. We hypothesize that these alterations in neurosteroidogenesis may contribute to the clinical phenotype. Our data show that appropriately timed treatment of NP-C mice with ALLO increases the lifespan of NP-C mice and delays the onset of neurological impairments that are hallmarks of this disease in mice - tremor, ataxia, and hindlimb dysfunction. Furthermore, ALLO treatment of NP-C mice significantly increases cerebellar Purkinje and granule cell survival and substantially reduces accumulation of cortical gangliosides GM1, GM2 and GM3. As a prerequisite for submission of an IND to the FDA for future clinical trials in children with NP-C, we propose to establish the.pharmacokinetics and pharmacodynamics of ALLO in wild type and NP-C mice, optimize ALLO treatment in NP-C mice, and generate toxicology safety data in animals. The use of neuro-active steroids in the treatment of degenerative brain diseases has not been described previously. We believe it is very possible that other brain diseases, including, but not limited to congenital storage diseases, may benefit from similar treatments with neuro-active steroids. Thus this proposal is directed toward the treatment of a broad group of disorders with a novel class of drugs, with NP-C as the model disease.
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