Therapy of Neuronopathic Gaucher Disease

描述(由申请人提供)：拟议的研究重点是针对高谢病神经病变变种的创新的临床前治疗方法：潜在的可筛查的先天性新陈代谢错误。拟议的研究使用研究人员独特的神经元病理性高谢病小鼠模型来解决这样的假设：原型竞争抑制剂，称为药理“伴侣”，或选定的有效底物合成抑制剂将在体内具有治疗作用。酸性葡萄糖苷酶(GCase)的活性不足启动了病理过程，而底物--葡萄糖神经酰胺(GC)或更重要的是对于中枢神经系统变异体--葡萄糖鞘氨醇(GS)的正常化对于防止或逆转疾病的进展是必不可少的。本应用的目的是评估选定的“伴侣”和葡萄糖神经酰胺合成酶(GCS)抑制剂对中枢神经系统区域特异性GC和GS存储的体内影响，以及它们的反应，使用在中枢存储这两种底物的神经病理性高谢病小鼠模型。这些小鼠携带一种改变的GCase，该酶在催化活性和/或溶酶体体外转运方面显示出可纠正的“伴侣”缺陷。将致力于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磷脂假说，并强调了减少所有有毒底物水平对疾病进程和发病机制的影响的重要性。这一结果将对新的/新的治疗方法和干预措施的时机产生影响，以便在未来通过新生儿筛查确定的疾病的人体试验中获得最佳疗效。 公共卫生相关性：这些研究致力于解决未得到满足的治疗影响大脑并导致退化的早发性疾病的医疗需求。拟议的研究将调查在特定工程小鼠中使用新的化学治疗方法来治疗模型疾病。这些结果对溶酶体储存疾病和相关的先天性新陈代谢错误有一定的影响。

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.