Therapy of Neuronopathic Gaucher Disease

描述（由申请人提供）：拟议的研究重点是戈谢病神经病变变体的创新临床前治疗：潜在的可筛选的先天性代谢缺陷。 拟议的研究使用研究人员独特的神经病理性戈谢病小鼠模型来解决以下假设：原型竞争性抑制剂，称为药理学“伴侣”，或选定的有效底物合成抑制剂将在体内治疗。 酸性葡糖苷酶（GCase）活性不足引发病理过程，CNS中底物-葡糖神经酰胺（GC）或更重要的CNS变体-葡糖鞘氨醇（GS）-流量的正常化对于预防或逆转疾病进展至关重要。 本申请的目的是评价所选“伴侣”和葡糖神经酰胺合酶（GCS）抑制剂对CNS区域特异性GC和GS储存的体内作用，以及它们使用在CNS中储存这两种底物的神经病性戈谢病的这些小鼠模型的反应。 这些小鼠携带改变的GCase，其在离体催化活性和/或溶酶体运输中表现出“伴侣”可校正的缺陷。 将努力确定校正细胞GC和GS代谢所需的CNS中GCase活性水平。 这些研究解决了溶血鞘脂假说，并强调了降低所有毒性底物水平以影响疾病进程和发病机制的重要性。 这些结果将对新的/新的治疗方法和干预措施的时机产生影响，以便在未来的新生儿期筛查确定的疾病人体试验中获得最佳疗效。 公共卫生相关性：这些研究奋进于解决影响大脑并导致退化的早发性疾病治疗的未满足的医疗需求。 拟议的研究将调查新的化学治疗方法在特别工程小鼠模型疾病的使用。 这些结果对溶酶体贮积病和相关的先天性代谢缺陷有意义。

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.