Developing Adjuvant SiRNA Therapy for Huntington's Disease

描述(申请人提供)：siRNAs是人工合成的约21个碱基对的双链寡核苷酸。当应用于细胞时，siRNAs可以有效和特异性地沉默他们的目标基因，称为RNA干扰(RNAi)。RNAi已成为功能基因组学极具吸引力的工具，也是一类潜在的人类治疗学分子。然而，几乎每家siRNA制药公司都遇到了几个障碍，主要是人体试验所需的高剂量siRNA，随之而来的是潜在的副作用，以及siRNA分子的靶外效应。后者被认为可以通过巧妙的siRNA分子设计来解决。对于前者，目前还没有解决方案。为了解决这些与siRNA治疗相关的困难，我们已经确定了一种RNAi增强子，它可以提高siRNA效率，降低所需的siRNA剂量，并延长其沉默效果。如果开发成功，这些增强剂可以作为siRNA药物的辅助治疗。亨廷顿病(HD)是一种罕见但致命的常染色体显性遗传性神经退行性疾病，由亨廷顿蛋白(Htt)编码基因的显性突变引起。在美国，大约有15,000到30,000人患有亨廷顿氏症。目前还没有逆转这种疾病发展的治疗方法。RNAi介导的突变Htt基因沉默是治疗HD的一种有前途的治疗方法。到目前为止，已经开发了两个用于治疗HD的siRNA。因此，目前用于HD的siRNA候选药物的全部疗效可能还没有实现。在这个第一阶段的STTR提案中，我们将在小鼠模型中检查RNAi-E是否可以增强siRNAs治疗HD的疗效，这将提供原理证明，RNAi-E可以与siRNA药物一起用作辅助治疗。我们将在体外系统中确定RNAi增强化合物(RNAi-E)的最佳浓度，以增强针对Htt的化学修饰的siRNA分子，并通过小鼠模型确定RNAi-E增强siRNA效率的可行性。该项目的第二阶段将包括使IND成为可能的配方、药代动力学和毒理学研究，以推动领先化合物(S)进入人体临床试验。如果这些研究成功，这将是朝着将siRNAs用于治疗试剂的改进迈出的一大步。与公共卫生相关：这项第一阶段的STTR应用集中在基于RNAi增强子的人类疾病siRNA药物辅助疗法的开发，该RNAi增强子可以提高siRNA效率，降低所需的siRNA剂量，并延长其沉默效果。拟议的研究将是朝着改进siRNAs用于治疗人类疾病的治疗试剂迈出的一大步。

DESCRIPTION (provided by applicant): SiRNAs are synthetic double-stranded oligonucleotides of ~21 base pairs. When applied to cells, siRNAs can effectively and specifically silence their target genes, called RNA interference (RNAi). RNAi has become attractive tool for functional genomics and a potential class of molecules for human therapeutics. However, almost every siRNA drug company encounters several hurdles, mainly the high dose of siRNA needed for human trials with which come potential side effects, and off-target effects of siRNA molecules. The latter is believed to be resolvable by clever design of siRNA molecules. There are no solutions for the former at the moment. To address these difficulties associated with siRNA therapy, we have identified an RNAi-enhancer that can raise siRNA efficacy, lower the required siRNA dose, and prolong its silencing effect. If successfully developed, these enhancers could be used as an adjuvant therapy with siRNA drugs. Huntington's disease (HD) is a rare but fatal autosomal dominant neurodegenerative disorder caused by dominant mutations in the genes encoding the protein huntingtin (Htt). There are approximately 15,000 to 30,000 people in the United States who suffer from Huntington's disease. Currently there is no treatment to reverse the progression of the disease. RNAi-mediated silencing of the mutated Htt genes is a promising therapeutic treatment for HD. To date, two siRNAs have been developed for the treatment of HD. As a result, the full efficacy of current siRNA drug candidates for HD may not yet be achieved. In this Phase I STTR proposal, we will examine whether RNAi-E can enhance the efficacy of siRNAs to treat HD in a mouse model, which will provide the proof-of-principle demonstration that RNAi-E could be used as an adjuvant therapy along with siRNA drugs. We will determine the optimal concentration of an RNAi-enhancing compound (RNAi-E) to potentiate chemically modified siRNA molecules targeting Htt in an in vitro system and determine the feasibility of RNAi-E for enhancing siRNA efficacy using a mouse model. Phase II of this project will entail IND enabling formulation, pharmacokinetics and toxicology studies that advance the leading compound(s) into human clinical trials. If these studies are successful, this would be a major stride toward the improvement of siRNAs for use as therapeutic reagents. PUBLIC HEALTH RELEVANCE: This Phase I STTR application is focused on the development of an adjuvant therapy with the siRNA drugs for human diseases based on the identification of an RNAi-enhancer that can raise siRNA efficacy, lower the required siRNA dose, and prolong its silencing effect. The proposed studies would be a major stride toward the improvement of siRNAs for use as therapeutic reagents to treat human diseases.