Developing Adjuvant SiRNA Therapy for Huntington's Disease

描述（由申请人提供）：siRNA是约21个碱基对的合成双链寡核苷酸。当应用于细胞时，siRNA可以有效地和特异性地沉默其靶基因，称为RNA干扰（RNAi）。RNAi已成为功能基因组学研究的重要工具，也是一类潜在的人类治疗分子。然而，几乎每个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，这会带来潜在的副作用，以及siRNA分子的脱靶效应。后者被认为可以通过siRNA分子的巧妙设计来解决。对于前者，目前还没有解决办法。为了解决与siRNA治疗相关的这些困难，我们已经鉴定了一种RNAi增强剂，其可以提高siRNA功效，降低所需的siRNA剂量，并延长其沉默效果。如果开发成功，这些增强子可以用作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神经退行性疾病，由编码亨廷顿蛋白（Htt）的基因的显性突变引起。在美国大约有15，000至30，000人患有亨廷顿病。目前没有治疗方法可以逆转疾病的进展。RNAi介导的突变Htt基因沉默是一种有前途的HD治疗方法。迄今为止，已经开发了两种siRNA用于治疗HD。因此，目前用于HD的siRNA候选药物的全部功效可能尚未实现。在这个I期STTR提案中，我们将检查RNAi-E是否可以增强siRNA在小鼠模型中治疗HD的功效，这将提供RNAi-E可以与siRNA药物一起用作沿着的原理证明。我们将确定RNAi增强化合物（RNAi-E）在体外系统中增强靶向Htt的化学修饰的siRNA分子的最佳浓度，并使用小鼠模型确定RNAi-E用于增强siRNA功效的可行性。该项目的第二阶段将需要IND使配方，药代动力学和毒理学研究，将领先的化合物推进人体临床试验。如果这些研究成功，这将是改善siRNA用作治疗试剂的一个重大进展。公共卫生相关性：该I期STTR申请专注于开发用于人类疾病的siRNA药物的辅助疗法，其基于可以提高siRNA功效、降低所需siRNA剂量并延长其沉默效应的RNAi增强剂的鉴定。拟议的研究将是改善siRNAs作为治疗人类疾病的治疗试剂的一个重大进展。

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.