Therapy of Gaucher Disease: In Vivo Enhancement of Residual Mutant Activity

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DESCRIPTION (provided by applicant): The proposed research focuses on innovative, preclinical therapies for the variants of Gaucher disease, a rare, but not uncommon, inborn error of metabolism. The proposed studies use our unique mouse models of Gaucher disease to address the hypotheses that prototype inhibitors of L-type Ca++ channels (LTCC) will enhance mutant GCase activity to therapeutic levels in vivo. The insufficient activity of acid -glucosidase [GCase] initiates the pathological processes, and normalization of substrate--glucosylceramide [GC] or glucosylsphingosine [GS] -- flux is essential to prevent or reverse disease progression. The objectives of this proposal are to evaluate the in vivo effects of selected LTCC inhibitors on mutant GCase activities and protein levels in various target organs and potential therapeutic responses using our unique mouse models of Gaucher disease. These mice bear an altered GCase that exhibits a LTCC inhibitor ex vivo correctible defect in catalytic activity and/or lysosomal trafficking. Efforts will be directed to defining the response levels of GCase activity and protein in liver, spleen, lung and CNS, the major organs involved in the Gaucher variants. In addition, CNS therapeutic responses to LTCC inhibitors will be evaluated in our unique viable subacute neuronopathic mouse model of Gaucher disease. Positive results from these preclinical studies would/could dramatically alter the approaches to therapy of many lysosomal storage diseases from enzyme, gene and substrate depletion strategies to molecular engineering of existent mutant enzymes in vivo using small, easily manufactured, oral agents. PUBLIC HEALTH RELEVANCE: RESEARCH & RELATED: These studies endeavor to address the unmet medical need of treatment for early onset diseases that effect the brain and lead to degeneration. The proposed studies will investigate the use of small molecule treatments for model diseases in specifically engineered mice with or without CNS disease. The outcomes have implications for the lysosomal storage diseases and related inborn errors of metabolism.