Tissue Adhesive RNA Interference Nanoparticles to Block Progression of Posttraumatic and Spontaneous Osteoarthritis.

组织粘附 RNA 干扰纳米颗粒可阻止创伤后和自发性骨关节炎的进展。

• 批准号: 10539405
• 负责人: Craig Lewis Duvall
• 金额: $ 62.21万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539405
• 关键词: Adhesions; Affect; Age-Months; Aging; Analgesics; Animal Model; Animals; Anterior Cruciate Ligament; Anti-Inflammatory Agents; Antibodies; Arthralgia; Benchmarking; Binding; Biological; Biology; Biomedical Engineering; Cartilage; Catalytic Domain; Cavia; Chemicals; Chemistry; Clinical; Clinical Trials; Collaborations; Collagen; Collagen Type II; Degenerative polyarthritis; Development; Diagnostic; Disease; Disease Progression; Doctor of Medicine; Doctor of Philosophy; Dose; Drug Delivery Systems; Drug Kinetics; Early treatment; Family suidae; Feedback; Formulation; Gene Silencing; Homologous Gene; Human; Immunology; In Vitro; Individual; Inflammatory; Injury; Interstitial Collagenase; Intervention; Investigational Therapies; Joints; Knee; Knee joint; Lead; Lesion; Life; Life Style Modification; Longevity; Masks; Matrix Metalloproteinases; Messenger RNA; Metabolic; Modeling; Molecular; Monoclonal Antibodies; Mus; Nanotechnology; Obesity; Outcome; Pain; Pathogenesis; Patient Care; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Polymers; Positioning Attribute; Production; Property; Proteins; Quality of life; RNA; RNA Interference; RNA Interference Therapy; Replacement Arthroplasty; Research Design; Resistance; Risk; Side; Signal Transduction; Site; Small Interfering RNA; Specificity; Steroids; Structural Protein; System; Testing; Therapeutic; Therapeutic Studies; Tissue Adhesives; Traumatic Arthropathy; Up-Regulation; Weight; Weight-Bearing state; articular cartilage; base; cancer clinical trial; cartilage degradation; clinical care; collagenase; collagenase 1; collagenase 3; cytokine; design; drug testing; guinea pig model; high risk; improved; in vivo; innovation; insight; joint function; joint injury; knock-down; ligament injury; mechanical load; nanomedicine; nanoparticle; pain relief; pharmacokinetics and pharmacodynamics; pre-clinical research; response to injury; rheumatologist; side effect; small molecule; small molecule inhibitor; treatment group

PROJECT SUMMARY/ABSTRACT Osteoarthritis (OA) results from a combination of natural wear and tear associated with aging and/or unnatural mechanical loading on the joint. Patients who suffer a joint injury (e.g., ligament damage) have increased risk for early development of OA. Injury-related post-traumatic osteoarthritis (PTOA) often occurs in younger patients. PTOA and OA are both associated with articular cartilage erosion and other joint changes that cause pain and loss in quality of life. The available treatments only provide temporary pain relief. However, alleviation of pain only briefly masks the disease and does not halt or slow its progression. Progression of PTOA/OA to the point where joint replacement becomes necessary is almost inevitable for large joints because there are currently no disease-modifying osteoarthritis drugs (DMOADs) that can stop progression of or cure the disease. Loss of cartilage associated with OA and PTOA is driven by local upregulation of matrix metalloproteinases (MMPs). We propose that blocking the cartilage-degrading MMPs could stop the progression of PTOA/OA, improve quality of life, and reduce the need for joint replacement in afflicted patients. Pharmaceutical companies have previously tested drugs that can block the activity of MMPs, but these treatments have failed, primarily because their lack of specificity and lack of delivery approaches that localize the drug to the affected joint. We propose to develop intra-articularly injected bioadhesive nanoparticles for locally-retained delivery of short interfering RNA (bioad-si-NPs). The bioad-si-NPs will potently and specifically “knock down” specific MMPs to halt cartilage degradation in joints with OA or at risk of OA development (following injury). The mechanism of siRNA enables these molecules to be selective for specific MMPs, and the bioad-si-NPs are designed to be retained locally at the site of intra-articular delivery; both of these features contribute to our approach having reduced risk of off target side effects. We will test bioad-si-NPs in animal models of both PTOA and spontaneous OA and for inhibition of single or combinations of MMPs. In the setting of spontaneous OA, we will also test the value of initiating treatment at early versus more advanced stages of disease. This project is uniquely accessible through the interdisciplinary team with bioengineering expertise in intracellular biologic drug delivery nanotechnologies and RNA chemistry (Duvall), OA biology and animals models (Hasty), analysis of PTOA/OA animal model joint function/pain (Krug), and clinical care of OA patients (Crofford).

项目摘要/摘要 骨关节炎（OA）是由与衰老和/或不自然相关的自然磨损组合的结果 关节上的机械载荷。遭受联合伤害的患者（例如韧带损伤）的风险增加 OA的早期发展。与伤害相关的创伤后骨关节炎（PTOA）经常发生在年轻患者中。 PTOA和OA都与关节软骨侵蚀以及其他引起疼痛和的关节变化有关 生活质量的损失。可用的治疗仅提供暂时缓解疼痛。但是，减轻疼痛 仅短暂地掩盖了该疾病，不会停止或减慢其进展。 PTOA/OA的进展到该点 对于大型关节而言，几乎需要更换关节的地方，因为目前没有 疾病改良的骨关节炎药物（DMOADS）可以阻止或治愈该疾病。 与OA和PTOA相关的软骨的损失是由基质金属蛋白酶的局部上调驱动的 （MMP）。我们建议阻止降解软骨的MMP可以阻止PTOA/OA的进展， 提高生活质量，并减少受患者的关节置换需求。制药公司 以前已经测试了可以阻止MMP活性的药物，但是这些治疗失败了，主要 因为他们缺乏特异性和缺乏将药物定位到受影响关节的输送方法。 我们建议开发关节内注射的生物粘附纳米颗粒，以局部固定的短递送 干扰RNA（BioAD-SI-NP）。 Bioad-Si-NP可能会有潜在地“击倒”特定的MMP 与OA的关节或有OA发育的风险（受伤后）停止软骨降解。机制 siRNA使这些分子能够选择特定的MMP，并且设计为BioAD-SI-NPS为 在关节内分娩部位保留；这两个功能都有助于我们的方法 降低了目标副作用的风险。我们将在PTOA和赞助的动物模型中测试BioAD-SI-NP OA并抑制MMP的单个或组合。在赞助OA的情况下，我们还将测试 在早期与更晚期疾病的启动治疗的价值。 通过跨学科团队具有生物工程专业知识，可以独特地访问该项目 生物药物输送纳米技术和RNA化学（DUVALL），OA生物学和动物模型（Hasty）， PTOA/OA动物模型联合功能/疼痛（KRUG）和OA患者的临床护理分析（Crofford）。