Albumin Binding siRNAs for Systemic Treatment of Multi-Joint Osteoarthritis

白蛋白结合 siRNA 用于多关节骨关节炎的全身治疗

• 批准号: 10358582
• 负责人: Craig Lewis Duvall
• 金额: $ 20.4万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-19 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358582
• 关键词: Adrenal Cortex Hormones; Affect; Aftercare; Age-Months; Aging; Albumins; Amyloidosis; Animal Model; Animals; Anterior Cruciate Ligament; Antibodies; Binding; Biological Assay; Biological Availability; Biology; Blood Vessels; Body Weight decreased; Cartilage; Cavia; Chemicals; Chondrocytes; Chronic; Clinical; Collagen; Collagen Type II; Complex; Degenerative Disorder; Degenerative polyarthritis; Deterioration; Development; Disease; Disease Progression; Dose; Drug Kinetics; Drug Targeting; Financial Hardship; Formulation; Fruit; Gene Expression; Gene Silencing; Genetic Medicine; Goals; Healthcare Systems; Hepatotoxicity; High Pressure Liquid Chromatography; Histologic; Human; In Situ; Inflammation; Inflammatory; Injury; International; Interstitial Collagenase; Intra-Articular Injections; Intravenous; Joints; Knee; Label; Limb structure; Lipids; Liver; Malignant Neoplasms; Matrix Metalloproteinase Inhibitor; Matrix Metalloproteinases; Measures; Mechanics; Metabolic; Methods; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Steroidal Anti-Inflammatory Agents; Organ; Outcome; Pain; Palliative Care; Peptide Hydrolases; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Plasma; Polyneuropathy; Porphyrias; Process; Quality of life; RNA Interference; Renal clearance function; Research; Saline; Secondary to; Serum; Severity of illness; Small Interfering RNA; Societies; Steroids; Stomach; Structural Protein; Synovial Fluid; Testing; Therapeutic; Therapeutic Index; Thinness; Time; Tissues; Toxic effect; Work; acute toxicity; analog; arthropathies; base; behavior test; cartilage degradation; clinical care; clinically relevant; clinically significant; cohort; collagenase; collagenase 1; collagenase 3; cytokine; design; fluorophore; gastrointestinal; guinea pig model; improved; innovation; insight; intravenous injection; intravital imaging; lipid nanoparticle; molecular drug target; mouse model; nanoformulation; nephrotoxicity; novel; pain relief; screening; side effect; small molecule; systemic toxicity; therapeutic evaluation; therapeutic siRNA; therapeutic target

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.

项目摘要/摘要 骨关节炎(OA)是一种影响关节及其周围组织的慢性退行性疾病。办公自动化可以 在创伤后骨关节炎(PTOA)的情况下，随着年龄的增长而自发发生，或继发于损伤。 办公自动化/临时办公造成严重的发病率和生活质量的损失，造成估计#年的财政负担。 美国每年超过440亿美元。非类固醇抗炎药通常是一线 治疗疼痛，但不会减缓软骨的退化，并可能导致胃肠道问题。这个 国际骨性关节炎研究学会建议使用皮质类固醇来暂时缓解疼痛，但 类固醇也不是针对疾病的根本原因，甚至可能会加剧软骨变薄。这些 缺点留下了对疾病修饰的OA/PTOA药物(DMOAD)的未得到满足的需求，这些药物可以阻断或减少 疾病的发展。在OA/PTOA中，滑膜细胞和软骨细胞产生炎性细胞因子和 推动关节退变过程的基质金属蛋白酶(MMPs)。小分子基质金属蛋白酶抑制剂 已经在临床上进行了癌症测试，但失败的主要原因是缺乏基质金属蛋白酶引起的全身毒性 选择性。RNA干扰是一种很有前途的策略，可用于创建靶向选择性治疗 很难给分子靶标下药。该项目的重点是开发和PTOA治疗测试 能够选择性地单独或联合抑制特定胶原酶的siRNA疗法。这个 提出的方法建立在我们最近开发通过聚乙二醇端修饰的siRNA分子的工作基础上 带有二酰基脂的接头(siRNA-L2)，它自发地与白蛋白(alb/)形成分子络合物。 SiRNA-L2)静脉注射后原位注射。这种白蛋白“搭便车”的siRNA-L2增强了siRNA PK，IS 非常安全，提高了给药水平和同质性，特别是对具有以下特征的组织 炎症和血管渗漏。该提案的总体目标是实现siRNA-L2以 系统地治疗和阻断PTOA的进展。该项目将评估siRNA-L2治疗指数在 PTOA小鼠模型，然后测试靶向单一与多种蛋白水解酶在豚鼠中的疾病疗效 猪PTOA模型。