Modulators of Rab9 Expression for the Treatment of Niemann-Pick C Disease

描述（由申请方提供）：NPC 1疾病是一种重度溶酶体变性，其中胆固醇和其他脂质从内体/溶酶体（E/L）系统中排出受阻，导致重度神经变性和过早死亡。 目前，NPC 1或其他溶酶体贮积症（LSD）患者没有治疗选择，这些患者存在神经退行性表型，这主要是由于纠正蛋白无法穿过血脑屏障。 因此，需要一种新的范式来解决LSD与神经病理学的大家族。 我们hypothesiae，抑制蛋白可以确定为LSDs和这些蛋白的表达可以通过小的化学分子，可以获得进入中枢神经系统，并限制这些疾病的严重程度进行调制。 本质上，这种方法绕过了有缺陷的溶酶体蛋白，因此我们将其称为“孤儿受体旁路疗法”或“ORByT”。 我们将首先进行高通量筛选，以确定NPC 1疾病的ORByT相关小分子的活性。 使用Rab 9作为NPC 1的“抑制剂”候选物，我们将使用最近建立的高通量筛选NPC 1疾病的抑制剂。 其次，我们将评估候选分子的治疗潜力。 将检测目标1中鉴定的小分子化合物纠正NPC 1脂质转运阻滞表型的能力。 将使用NPC小鼠模型在体内评价那些被证实恢复NPC细胞中脂质转运的化合物，以在进一步开发以改善其效力、毒性特征和脑递送之前确定其治疗潜力。 小分子的成功鉴定将为ORByt策略提供“原理证明”，并为NPC 1和其他破坏性神经LSD的治疗提供新方法。 公共卫生相关性：影响大脑的疾病目前很难治疗，如果不是不可能的话。我们正在开发一种新的方法来治疗目前无法治疗的神经系统受累的毁灭性遗传疾病。

DESCRIPTION (provided by applicant): NPC1 disease is a severe lysosomal lipidosis in which the egress of cholesterol and other lipids from the endosomal/lysosomal (E/L) system is impeded, leading to severe neurodegeneration and premature demise. At present there are no treatment options for patients with NPC1 or other lysosomal storage disorders (LSDs) that present with neurodegenerative phenotypes, mainly due to the inability of corrective proteins to cross the blood-brain barrier. Therefore, a new paradigm is needed to address the large family of LSDs with neuropathology. We hy7pothesiae that suppressor proteins can be identified for the LSDs and that the expression of these proteins can be modulated via small chemical molecules that can gain access to the central nervous system and limit the severity of these disorders. In essence, this approach bypasses the defective lysosomal protein and therefore we have termed it "Orphan receptor bypass therapy" or "ORByT". We will first carry out a high-throughput screen to identify pharmacologically active, for ORByT-relevant small molecules for NPC1 disease. Using Rab9 as a "suppressor" candidate for NPC1, we will use the recently established high throughput screening pharmacologically active for NPC1 disease. Second, we will evaluate candidate molecules for the therapeutic potential. Small molecule compounds identified in Aim 1 will be tested for their ability to correct the NPC1 lipid transport block phenotype. Those compounds that are confirmed to restore lipid transport in NPC cells will be evaluated in vivo using an NPC mouse model to determine their therapeutic potential prior to further development to improve their potency, toxicity profile, and brain delivery. Successful identification of small molecules will provide "Proof-of-principle" for the ORByt strategy and a new approach to therapy for NPC1 and other devastating neurological LSDs. PUBLIC HEALTH RELEVANCE: Diseases that affect the brain are currently difficult if not impossible to treat. We are developing a novel approach to treat devastating genetic diseases with neurologic involvement that are currently untreatable.