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

基本信息

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
项目类别：
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

项目摘要

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。 OA可以在创伤后骨关节炎（PTOA）的情况下，随着衰老而自发发生或继发损伤。 OA/PTOA会导致明显的发病率和生活质量丧失，导致估计的财务燃烧美国每年超过440亿美元。非甾体类抗炎药通常是第一行处理疼痛的治疗方法，但不会减慢软骨的决定并可能导致胃肠道问题。骨关节炎研究协会国际建议皮质类固醇缓解临时疼痛，但类固醇也不针对疾病的根本原因，甚至可能担心软骨变薄。这些缺点使对疾病改良的OA/PTOA药物（DMOADS）的不满意，以阻止或减少疾病进展。在OA/PTOA中，滑膜细胞和软骨细胞产生炎症细胞因子和驱动关节退行过程的基质金属蛋白酶（MMP）。小分子MMP抑制剂已经在临床上进行了癌症测试，但在很大程度上失败了，由于缺乏MMP引起的全身毒性选择性。 RNA干扰是建立目标选择性治疗的承诺策略难以吸毒分子靶标。该项目的重点是开发和PTOA治疗测试可以选择性地抑制特定胶原酶的siRNA治疗，无论是单独还是组合。这提出的方法是根据我们最近开发的siRNA分子通过钉终止修饰的siRNA分子而建立的带有二酰基脂质（siRNA-L2）的连接器，它赞助形成与白蛋白的分子复合物（Alb/ 静脉注射后原位siRNA-L2）。这张专辑“ Hitchhiking” sirna-L2增强了sirna pk，是非常安全，并提高了分娩的水平和均匀性，特别是以炎症和血管泄漏。该提议的总体目标是将sirna-l2实施系统地处理和阻止PTOA的进展。该项目将评估siRNA-L2治疗指数 PTOA小鼠模型，然后测试靶向单蛋白酶与多种蛋白酶的疾病效率 PIG PTOA模型。