Therapy of Neuronopathic Gaucher Disease

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The proposed research focuses on innovative, preclinical therapies for the neuronopathic variants of Gaucher disease: potentially screenable inborn errors of metabolism. The proposed studies use the investigators' unique mouse model of neuronopathic Gaucher disease to address the hypotheses that: prototype competitive inhibitors, termed pharmacologic "chaperones," or selected potent substrate synthesis inhibitors will be therapeutic in vivo. The insufficient activity of acid ¿-glucosidase (GCase) initiates the pathological processes, and normalization of substrates--glucosylceramide (GC) or, more importantly for CNS-variants, glucosylsphingosine (GS) -- flux in CNS is essential to prevent or reverse disease progression. The objectives of this application are to evaluate the in vivo effects of selected "chaperones" and glucosylceramide synthase (GCS) inhibitors on CNS region-specific GC and GS storage, and their responses using these mouse models of neuronopathic Gaucher disease that store both these substrates in the CNS. These mice bear an altered GCase that exhibits a "chaperone"-correctible defect in catalytic activity and/or lysosomal trafficking ex vivo. Efforts will be directed to defining the levels of GCase activity in CNS needed to correct cellular GC and GS metabolism. These studies address the lysosphingolipid hypothesis and highlight the importance of diminishing the levels of all toxic substrates to affect the disease course and pathogenesis. The results will have implications for novel/new therapies and the timing of interventions for optimal efficacy in future human trials for diseases identified by screening in the newborn period. PUBLIC HEALTH RELEVANCE: These studies endeavor to address the unmet medical need of treatment for early onset diseases that affect the brain and lead to degeneration. The proposed studies will investigate the use of new chemical treatments for model diseases in specifically engineered mice. The outcomes have implications for the lysosomal storage diseases and related inborn errors of metabolism.