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

项目摘要/摘要 骨关节炎(OA)是自然老化和/或非自然磨损的综合结果。 关节上的机械载荷。遭受关节损伤(如韧带损伤)的患者患上 办公自动化的早期发展。创伤后骨关节炎(PTOA)通常发生在较年轻的患者中。 PTOA和OA都与关节软骨侵蚀和其他关节变化有关，这些变化会导致疼痛和 生活质量的下降。现有的治疗方法只能暂时缓解疼痛。然而，疼痛的缓解 只是短暂地掩盖了疾病，并没有阻止或减缓其进展。PTOA/OA进展到这一点 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 可以阻止疾病发展或治愈疾病的治疗骨关节炎的药物(DMOADs)。 与骨性关节炎和骨性关节炎相关的软骨丢失是由基质金属蛋白酶局部上调引起的 (MMPs)。我们认为，阻断软骨降解的MMPs可以阻止PTOA/OA的进展， 提高生活质量，减少患者关节置换术的需求。制药公司 之前曾测试过可以阻断MMPs活性的药物，但这些治疗方法主要是失败的 因为他们缺乏特异性，也缺乏将药物定位于受影响关节的给药方法。 我们建议开发关节内注射的生物黏附纳米粒，用于局部滞留传递 干扰RNA(Bioad-si-NPs)。这些生物广告-硅-NPs将有力地、特别地“击倒”特定的MMP以 阻止患有骨性关节炎或有骨性关节炎发展风险的关节软骨退化(损伤后)。它的作用机制 SiRNA使这些分子对特定的MMPs具有选择性，而生物ad-si-NPs被设计成 保留在关节内分娩的局部部位；这两个特征都有助于我们的方法 降低了偏离目标的副作用风险。我们将在PTOA和自发性的动物模型中测试生物ad-si-nps。 OA和抑制MMPs的单一或组合。在自发的办公自动化的设置中，我们也将测试 在疾病的早期阶段开始治疗与在更晚期阶段开始治疗的价值。 该项目通过具有细胞内生物工程专业知识的跨学科团队独一无二地实现 生物药物传递纳米技术和RNA化学(杜瓦尔)，骨关节炎生物学和动物模型(哈蒂)， 分析PTOA/OA动物模型关节功能/疼痛(Krug)，以及OA患者的临床护理(Crofford)。

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).