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).

项目总结/摘要 骨关节炎（OA）是由与衰老相关的自然磨损和/或非自然磨损的组合引起的。 关节上的机械载荷。遭受关节损伤的患者（例如，韧带损伤）的风险增加 OA的早期发展损伤相关的创伤后骨关节炎（PTOA）通常发生在年轻患者中。 PTOA和OA都与关节软骨侵蚀和其他引起疼痛的关节变化有关， 生活质量的损失。现有的治疗方法只能暂时缓解疼痛。然而，减轻疼痛 只是短暂地掩盖了疾病，并不能阻止或减缓其进展。PTOA/OA进展至 对于大关节来说，关节置换几乎是不可避免的，因为目前没有 疾病缓解骨关节炎药物（DMOAD），可以阻止疾病的进展或治愈疾病。 与OA和PTOA相关的软骨损失是由基质金属蛋白酶的局部上调驱动的 （MMPs）。我们认为阻断软骨降解MMPs可以阻止PTOA/OA的进展， 提高生活质量，减少患者对关节置换的需求。制药公司 以前曾测试过可以阻断MMP活性的药物，但这些治疗都失败了，主要是 因为它们缺乏特异性和缺乏将药物定位于受影响关节的递送途径。 我们建议开发关节内注射的生物粘附性纳米颗粒，用于局部保留递送短的 干扰RNA（bioad-si-NPs）。生物广告-纳米颗粒将有效地和特异性地“击倒”特定的MMP， 阻止患有OA或有OA发展风险的关节（损伤后）的软骨退化。的机理 siRNA使这些分子能够对特定的MMP具有选择性，并且bioad-si-NP被设计为 保留在关节内输送部位;这两个特征都有助于我们的方法具有 降低脱靶副作用的风险。我们将在PTOA和自发性PTOA的动物模型中测试bioad-si-NPs。 OA和抑制单一或MMPs的组合。在自发性OA的情况下，我们还将测试 在疾病的早期与更晚期阶段开始治疗的价值。 这个项目是唯一通过跨学科的团队与生物工程专业知识，在细胞内 生物药物递送纳米技术和RNA化学（杜瓦尔），OA生物学和动物模型（Hasty）， 分析PTOA/OA动物模型关节功能/疼痛（Krug），和OA患者的临床护理（Crofford）。