Developing Small Molecules to Potentiate RNA Interference

开发小分子以增强 RNA 干扰

• 批准号: 8044971
• 负责人: Peng Jin
• 金额: $ 3.36万
• 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/8044971
• 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.

描述（由申请人提供）：siRNA是〜21碱基对的合成双链寡核苷酸。当应用于细胞时，siRNA可以有效，特别明确地沉默其靶基因，称为RNA干扰（RNAi）。 RNAi已成为功能基因组学和人类疗法的潜在分子类别的有吸引力的工具。但是，几乎每个siRNA药物公司都遇到了几个障碍，主要是人类试验所需的高剂量siRNA，这些试验带来了潜在的副作用，以及siRNA分子的非目标效应。据信，后者可以通过智能设计的siRNA分子设计来解决。目前没有解决方案。为了解决与siRNA治疗相关的这些困难，我们已经确定了一个可以提高siRNA功效，降低所需siRNA剂量并延长其沉默效果的RNAi-Enhancer。如果成功开发，这些增强剂可以用作siRNA药物的辅助治疗。与年龄相关的黄斑变性（AMD）是黄斑露叶氏细胞变性的条件，导致视力模糊并最终导致失明。 AMD是50岁以上人失明的主要原因，每年在美国报告200,000例新病例。迄今为止，已经开发了两个siRNA用于治疗AMD。结果，可能尚未实现当前siRNA药物候选物的全部功效。在此I阶段的STTR提案中，我们将检查RNAI-E是否可以增强siRNA在小鼠模型中处理AMD的功效，该模型将提供原则证明RNAI-E可以用作辅助治疗和siRNA药物。我们将确定RNAI增强化合物（RNAI-E）的最佳浓度，以增强体外系统中化学改性的siRNA分子，并确定RNAI-E在体内增强siRNA疗效的可行性。该项目的第二阶段将需要提高配方，药代动力学和毒理学研究，这些研究将领先的化合物推向人类临床试验。如果这些研究成功，这将是朝着改善用作治疗试剂的改善的主要大步。