Developing Small Molecules to Potentiate RNA Interference

开发小分子以增强 RNA 干扰

• 批准号: 7744260
• 负责人: Peng Jin
• 金额: $ 11.54万
• 依托单位: EFFIGENE PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7744260
• 关键词: Address; Adjuvant Therapy; Adverse effects; Age; Age related macular degeneration; Animal Model; Antineoplastic Agents; Apoptosis; Architecture; Asthma; Base Pairing; Blindness; Blurred vision; Case Study; Cell Maintenance; Cells; Cholesterol; Chromosomes; Clinical Trials; Communicable Diseases; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Dose; Double-Stranded RNA; Drug Formulations; Drug Kinetics; Enhancers; Future; Gene Expression; Gene Targeting; Growth and Development function; HIV; Hepatitis B Virus; Hepatitis C virus; Human; Hypersensitivity; In Vitro; Marketing; MicroRNAs; Modeling; Mus; Neurons; Oligonucleotides; Parkinson Disease; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; RNA Interference; Reagent; Retina; Retinal macula; Shapes; Simplexvirus; Small Business Technology Transfer Research; Small Interfering RNA; Small RNA; Solutions; Stem cells; System; Therapeutic; Toxicology; Untranslated RNA; Vascular Endothelial Growth Factor Receptor-2; aging population; base; design; drug candidate; functional genomics; human disease; in vivo; mRNA Transcript Degradation; malignant breast neoplasm; mouse model; neovascular; novel therapeutics; public health relevance; small molecule; tool

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. Age-related macular degeneration (AMD) is a condition in which cells of the macula lutea degenerate, resulting in blurred vision and ultimately blindness. AMD is the leading cause of blindness in people over age 50, with 200,000 new cases reported annually in US. To date, two siRNAs have been developed for the treatment of AMD. As a result, the full efficacy of current siRNA drug candidates for AMD 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 AMD 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 in an in vitro system and determine the feasibility of RNAi-E for enhancing siRNA efficacy in vivo. 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.

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 可以有效且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的有吸引力的工具和人类治疗的一类潜在分子。然而，几乎每家siRNA制药公司都会遇到一些障碍，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。目前还没有针对前者的解决方案。为了解决与 siRNA 治疗相关的这些困难，我们发现了一种 RNAi 增强剂，可以提高 siRNA 功效、降低所需 siRNA 剂量并延长其沉默效果。如果开发成功，这些增强剂可用作 siRNA 药物的辅助治疗。年龄相关性黄斑变性（AMD）是黄斑细胞退化的一种疾病，导致视力模糊并最终失明。 AMD 是 50 岁以上人群失明的主要原因，美国每年报告 20 万例新病例。迄今为止，已经开发出两种 siRNA 用于治疗 AMD。因此，当前 siRNA 候选药物治疗 AMD 的全部功效可能尚未实现。在此一期 STTR 提案中，我们将研究 RNAi-E 是否可以增强 siRNA 在小鼠模型中治疗 AMD 的功效，这将为 RNAi-E 可以与 siRNA 药物一起用作辅助治疗提供原理证明。我们将确定 RNAi 增强化合物 (RNAi-E) 的最佳浓度，以在体外系统中增强化学修饰的 siRNA 分子，并确定 RNAi-E 在体内增强 siRNA 功效的可行性。该项目的第二阶段将需要进行 IND 配方、药代动力学和毒理学研究，以将先导化合物推进人体临床试验。如果这些研究成功，这将是改进 siRNA 作为治疗试剂的一大进步。公共健康相关性：这一期 STTR 申请的重点是开发一种用于人类疾病的 siRNA 药物辅助疗法，其基础是鉴定出一种 RNAi 增强剂，该增强剂可以提高 siRNA 功效、降低所需 siRNA 剂量并延长其沉默效果。拟议的研究将是朝着改进 siRNA 作为治疗人类疾病的治疗试剂迈出的一大步。