Albumin Binding siRNAs for Systemic Treatment of Multi-Joint Osteoarthritis

项目概要/摘要 骨关节炎（OA）是一种慢性退行性疾病，影响关节及其周围组织。OA可以 随着年龄的增长自发发生，或者在创伤后骨关节炎（PTOA）的情况下继发于损伤。 OA/PTOA会导致严重的发病率和生活质量的下降，导致估计的经济负担， 美国每年超过440亿美元。非甾体类抗炎药通常是 治疗，以处理疼痛，但不减缓软骨退化，并可能导致胃肠道问题。的 国际骨关节炎研究协会建议使用皮质类固醇暂时缓解疼痛， 类固醇也不针对疾病的根本原因，甚至可能使软骨变薄恶化。这些 这些缺点使得对疾病修饰OA/PTOA药物（DMOAD）的需求未得到满足， 疾病进展。在OA/PTOA中，滑膜细胞和软骨细胞产生炎性细胞因子， 基质金属蛋白酶（MMPs）驱动关节退行性过程。小分子MMP抑制剂 已经在临床上进行了癌症测试，但主要由于缺乏MMP引起的全身毒性而失败 选择性RNA干扰是一种很有前途的策略，用于创建靶向选择性治疗剂， 很难对分子靶点进行药物治疗。该项目的重点是开发和PTOA治疗测试， siRNA治疗剂可以单独或组合选择性地抑制特定的胶原酶。的 提出的方法建立在我们最近的工作开发siRNA分子末端修饰通过PEG 连接子与二酰基脂质（siRNA-L2），其自发地与白蛋白（alb/ siRNA-L2）。这种白蛋白“搭便车”siRNA-L2增强siRNA PK， 非常安全，并增加了递送的水平和均匀性，特别是对特征在于 炎症和血管渗漏。该提案的总体目标是实施siRNA-L2， 并阻断PTOA进展。该项目将评估siRNA-L2治疗指数， PTOA小鼠模型，然后在豚鼠中测试靶向单一蛋白酶与多种蛋白酶的疾病功效 猪PTOA模型。

Project Summary / Abstract Osteoarthritis (OA) is a chronic degenerative disease that affects joints and their surrounding tissues. OA can occur spontaneously with aging or be secondary to injury in the case of post-traumatic osteoarthritis (PTOA). OA/PTOA causes significant morbidity and loss of quality of life, resulting in an estimated financial burden in the U.S. of over $44 billion annually. Non-steroidal anti-inflammatory drugs are typically the first line of treatment to deal with pain but do not slow cartilage deterioration and can cause gastrointestinal problems. The Osteoarthritis Research Society International recommends corticosteroids for temporary pain relief, but steroids also do not target the underlying cause of disease and may even worsen cartilage thinning. These shortcomings leave an unmet need for disease-modifying OA/PTOA drugs (DMOADs) that block or reduce disease progression. In OA/PTOA, synoviocytes and chondrocytes produce inflammatory cytokines and matrix metalloproteinases (MMPs) that drive the joint degenerative process. Small molecule MMP inhibitors have been tested clinically for cancer but failed largely due to systemic toxicities caused by the lack of MMP selectivity. RNA interference is a promising strategy for creation of target selective therapeutics against difficult to drug molecular targets. This project is focused on development and PTOA therapeutic testing of siRNA therapeutics that can selectively inhibit specific collagenases, either alone or in combination. The proposed approach builds from our recent work developing siRNA molecules end-modified through a PEG linker with a diacyl lipid (siRNA-L2), which spontaneously forms a molecular complex with albumin (alb/ siRNA-L2) in situ following intravenous injection. This albumin “hitchhiking” siRNA-L2 enhances siRNA PK, is very safe, and increases level and homogeneity of delivery, particularly to tissues characterized by inflammation and vascular leakiness. The overall goal of this proposal is to implement siRNA-L2 to systemically treat and block progression of PTOA. This project will assess siRNA-L2 therapeutic index in a PTOA mouse model and then test the disease efficacy of targeting single versus multiple proteases in a guinea pig PTOA model.