Substrate Reduction Therapies for Niemann-Pick C Disease

描述（由申请方提供）：溶酶体贮积症是一种致死性遗传疾病，由与内体-溶酶体系统相关的多种蛋白质缺陷引起。C型尼曼-皮克病（NPC）是一种胆固醇-鞘糖脂（GSL）储存障碍，最常见的是NPC 1和NPG 2缺陷引起的，NPC 1是一种跨膜蛋白，被认为在从溶酶体的底物的反内吞运输中起关键作用，NPG 2是一种功能未知的可溶性溶酶体蛋白。缺乏任何一种蛋白质都会导致基本相同的病症，受影响的儿童在4-6岁时开始表现出进行性神经功能衰退，并在生命的第二个十年中死亡。治疗方面的一个重要观察结果是，受影响的儿童在出生时通常表现正常，只有在细胞内储存和代谢中断的阈值被超过后，才会出现临床症状。这一重要特征表明，出生后存在一个机会窗口，此时旨在纠正代谢缺陷的治疗可能会将细胞从疾病命运中拯救出来，从而改善或预防脑功能障碍。然而，NPC疾病的治疗选择非常有限，酶替代和细胞介导的治疗几乎没有希望提供益处，特别是对于NPC 1缺乏症，因为这种蛋白质不是由细胞分泌的。即使基因治疗也可能只对转导细胞有益，因为细胞之间缺乏NPC 1蛋白的转移。这些明显的局限性推动了一种新的治疗选择的发展-可以限制大脑和其他器官中有害底物积聚的药物-被称为底物减少疗法（SRT）。这里的初始方法是GSL合成的小分子抑制剂（N-丁基脱氧野尻霉素，Zelecca（r）），我们率先将其作为NPC疾病的治疗。最近的一项发现表明，一种天然存在的化合物，称为别孕烯醇酮（ALLO）的胆固醇衍生的神经类固醇，具有类似的限制NPC疾病中溶酶体储存的能力。虽然ALLO能够实现这种效果的机制尚不清楚，但最近的研究结果表明，一个关键特征是它能够作为胆甾烷X受体（PXR）的配体，从而对许多基因（包括控制固醇合成的基因）施加转录控制。我们研究的总体目标是使用NPC小鼠模型优化SRT剂的给药和功效，测试更多的候选PXR-配体化合物并确定它们对胆固醇和GSL积累的作用，并确定联合使用SRT剂是否会导致在延迟和/或预防NPC疾病的临床恶化方面更大的功效。除了测试与NPC受影响儿童直接和实际相关的疗法外，这些研究还将进一步探索NPC疾病中GSL储存和胆固醇之间的联系及其与NPC 1和NPC 2蛋白功能的关系。

DESCRIPTION (provided by applicant): Lysosomal storage disorders are fatal genetic diseases caused by defects in a wide range of proteins associated with the endosomal-lysosomal system. Niemann-Pick type C (NPC) disease is a cholesterol- glycosphingolipid (GSL) storage disorder caused most commonly by defects in NPC1, a transmembrane protein believed critical in retroendocytic trafficking of substrates from lysosomes, and in NPG2, a soluble lysosome protein of unknown function. Absence of either protein causes an essentially identical condition with affected children exhibiting progressive neurological decline beginning at 4-6 years of age and with death occurring in the second decade of life. An important observation in terms of therapy is that affected children most often appear normal at birth and only later, after a threshold of intracellular storage and metabolic disruption has been exceeded, do clinical symptoms develop. This important feature indicates that there is a window of opportunity after birth when therapy aimed at correction of the metabolic defect could potentially rescue cells from their disease fate and thereby ameliorate or prevent brain dysfunction. Therapeutic options for NPC disease, however, are very limited, with enzyme replacement and cell-mediated therapies providing little hope of benefit, particularly for NPC1 deficiency since this protein is not secreted by cells. Even gene therapy will likely only be beneficial to transduced cells again due to the lack of transfer of the NPC1 protein between cells. These clear limitations have driven development of a new therapeutic option - drugs that can limit the build-up of offending substrates in brain and other organs - known as substrate reduction therapy (SRT). An initial approach here was a small molecule inhibitor of GSL synthesis (N-butyldeoxnorjirimycin, Zavesca(r)) which we pioneered as a therapy for NPC disease. A more recent finding suggests that a naturally occurring compound, the cholesterol-derived neurosteroid known as allopregnanolone (ALLO), has a similar ability to limit lysosomal storage in NPC disease. While the mechanism by which ALLO is able to achieve this effect is unknown, recent findings suggest a critical feature is its ability to act as a ligand for the pregnane X receptor (PXR) and thereby to exert transcriptional control over numerous genes, including those controlling sterol synthesis. The overall goals of our study are to optimize the administration and efficacy of SRT agents using the NPC mouse models, to test an expanded number of candidate PXR-ligand compounds and determine their effects, on cholesterol and GSL accumulation, and to determine whether the-use of SRT agents in combination will lead to even greater efficacy in delaying and/or preventing clinical deterioration in NPC disease. In addition to testing therapies of direct and practical relevance to NPC-affected children, these studies will also further explore the linkage between storage of GSLs and cholesterol in NPC disease and their relationship to NPC1 and NPC2 protein function.