Therapy of Neuronopathic Gaucher Disease

描述（由申请人提供）：拟议的研究侧重于戈谢病神经病变变体的创新临床前治疗：潜在可筛查的先天性代谢错误。拟议的研究使用研究者独特的神经病变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”，或选择有效的底物合成抑制剂将在体内治疗。酸-葡萄糖苷酶（GCase）活性不足启动了病理过程，而底物-葡萄糖神经酰胺（GC）或更重要的CNS变体-葡萄糖鞘苷(GS) -在CNS中的通量的正常化对于预防或逆转疾病进展至关重要。本应用程序的目的是评估选定的“伴侣”和葡萄糖基神经酰胺合成酶（GCS）抑制剂对中枢神经系统区域特异性GC和GS储存的体内影响，以及它们在中枢神经系统储存这两种底物的神经病变戈谢病小鼠模型中的反应。这些小鼠携带改变的GCase，在体外催化活性和/或溶酶体运输中表现出“伴侣”可纠正的缺陷。我们将努力确定中枢神经系统中纠正细胞GC和GS代谢所需的GCase活性水平。这些研究解决了溶鞘脂假说，并强调了降低所有有毒底物水平以影响疾病病程和发病机制的重要性。这些结果将对在新生儿时期通过筛查确定的疾病的未来人体试验中产生最佳疗效的新疗法和干预时机产生影响。

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.