Substrate Reduction Therapies for Niemann-Pick C Disease

溶酶体贮积症是一种致命的遗传性疾病，由多种蛋白质的缺陷引起 与内体-溶酶体系统相关。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由NPC 1缺陷引起的，NPC 1是一种跨膜蛋白， 蛋白质被认为在底物从iys 6s 6 mes的逆向运输中起关键作用，并且在NPG 2中，一种可溶性 功能未知的溶酶体蛋白。任何一种蛋白质的缺乏都会导致与 4-6岁开始表现出进行性神经功能衰退并死亡的受影响儿童 发生在生命的第二个十年。治疗方面的一个重要观察结果是， 大多数通常在出生时表现正常，只有在细胞内储存和代谢的阈值之后， 已经超过中断，临床症状是否出现。这一重要特征表明伊萨 出生后的机会窗口，旨在纠正代谢缺陷的治疗可能 拯救细胞免于疾病命运，从而改善或预防脑功能障碍。治疗选择 然而，对于NPC疾病的治疗非常有限，酶替代和细胞介导的治疗提供了 几乎没有希望受益，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。即使是gene 由于缺乏NPC 1蛋白的转移， 细胞之间。这些明显的局限性推动了一种新的治疗选择的发展-药物， 限制有害物质在大脑和其他器官中的积聚-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-丁基脱氧去甲野尻霉素， Zalca），我们率先作为一种治疗NPC疾病。最近的一项研究表明， 发生的化合物，胆固醇衍生的神经类固醇称为别孕烯醇酮（ALLO），具有类似的 限制NPC疾病中溶酶体储存的能力。虽然ALLO能够实现这一目标的机制 效果是未知的，最近的研究结果表明，一个关键的特点是它的能力，作为一个配体的甾烷X 受体（PXR），从而对许多基因，包括那些控制 甾醇合成我们研究的总体目标是优化SRT药物的管理和疗效 使用NPC小鼠模型，测试更多的候选PXR-配体化合物， 确定它们对胆固醇和GSL积累的影响，并确定是否使用SRT 药物联合使用将在延迟和/或预防临床恶化方面产生更大的功效 NPC疾病。除了测试与NPC受影响儿童直接和实际相关的疗法外， 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， 它们与NPC 1和NPC 2蛋白功能的关系。

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 retroehdbcyWtrafficking of substrates from iys6s6mes,'ahd 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 isa 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¿) 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 exerttranscriptional 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.