Repurposing Alpha-1-antitrypsin as a treatment for post-traumatic osteoarthritis

重新利用 Alpha-1-抗胰蛋白酶治疗创伤后骨关节炎

• 批准号: MR/Y013883/1
• 负责人: Mauro Perretti
• 金额: $ 72.19万
• 依托单位: Queen Mary University of London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2024
• 资助国家: 英国
• 起止时间: 2024 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FY013883%2F1
• 关键词: Repurposing; Alpha; antitrypsin; treatment; post; Repurposing; Alpha; antitrypsin; treatment; post

Osteoarthritis (OA) is the most common joint disease that causes chronic pain and disability in hundreds of millions of people globally. Our joints work because there is a special tissue layer, called cartilage, which maintains the edge of the bones smooth and avoids attrition. If cartilage is broken down by traumatic events or eroded by ageing and also micro-traumas, there is disease characterized by joint malfunctioning (lack of mobility) and excruciating pain. Here we focus on trauma-induced ligament or cartilage injuries which contributes to over 12% of the overall OA burden worldwide: a significant proportion of these patients (~40%) develop osteoarthritis even with the best available treatments. Surgical stabilisation of the joint is the treatment for trauma-induced ligament or cartilage injuries; however, research indicates that ongoing inflammation following surgical stabilization plays a crucial role in driving progression to osteoarthritis. Therefore, we propose that early intervention with factors that mitigate inflammation and promote cartilage repair after joint injury can prevent further damage and the development of post-traumatic osteoarthritis. We have identified one such factors, and it is termed alpha1-antitrypsin (AAT).With this proposal we seek funding to study the fundamental biology of AAT in experimental post-traumatic osteoarthritis; understanding how it works can open innovative therapeutic approaches for better management of osteoarthritis. This hypothesis will be tested by three experimental objectives.1. Study the molecular mechanisms of AAT using human chondrocytes, the cells that produce the cartilage. We aim to unravel how AAT stimulates cartilage growth to repair post-traumatic defects. This involves investigating AAT interaction with counterparts on the cell surface (often called receptors) and study what happens within the cell after the interaction takes place.2. Evaluate the potential of AAT for therapeutic repair of cartilage damage. We will conduct experiments using an approved AAT product called Prolastin-C to assess its efficacy in regenerating damaged cartilage and bone defects. Our research will involve laboratory tests as well as pre-clinical models of post-traumatic osteoarthritis.3. Investigate the role of endogenous AAT on cartilage regeneration. Here we will use mice genetically modified to lack the genes that produce AAT. These animals are commercially available and viable. We will apply them to our model of joint injury, to assess if and how naturally occurring AAT contributes to cartilage maintenance and repair in the context of joint injuries.At completion this project may identify AAT as a novel disease-modifying osteoarthritic drug. Since Prolastin-C (plasma AAT, produced by Grifols) is already used to treat lung disease in individuals with the rare genetic deficiency in AAT, we reason that this project can guide a rapid repurposing trial for this new therapeutic agent. In summary, we aim to uncover the mechanisms by which AAT influences chondrocytes and promotes cartilage repair with human cells and animals with osteoarthritis. At project completion, and with further funding support, our ultimate objective is to develop AAT-based drugs that can slow down the progression of osteoarthritis and provide long-term relief for individuals suffering from the condition.

骨关节炎（OA）是最常见的关节疾病，在全球数亿人中引起慢性疼痛和残疾。我们的关节之所以起作用，是因为有一个特殊的组织层，称为软骨，它可以保持骨骼的边缘光滑并避免损耗。如果软骨被创伤事件分解或因衰老和微创伤而侵蚀，则具有关节功能故障（缺乏迁移率）和令人难以置信的疼痛的疾病。在这里，我们专注于创伤引起的韧带或软骨损伤，这造成了全球总体OA负担的12％以上：这些患者中有很大一部分（约40％）患有骨关节炎，即使有最佳的治疗方法。关节的手术稳定是治疗创伤诱导的韧带或软骨损伤的治疗方法。但是，研究表明，手术稳定后正在进行的炎症在推动骨关节炎的发展中起着至关重要的作用。因此，我们建议早期干预关节损伤后减轻炎症和促进软骨修复的因素可以防止进一步的损害和创伤后骨关节炎的发展。我们已经确定了一个这样的因素，它称为alpha1-抗丁硫蛋白酶（AAT）。我们在此提案中寻求资金来研究AAT在实验性创伤后骨关节炎中的基本生物学；了解其工作方式可以打开创新的治疗方法，以更好地管理骨关节炎。该假设将通过三个实验目标进行检验1。使用人体软骨细胞（产生软骨的细胞）研究AAT的分子机制。我们旨在揭示AAT如何刺激软骨生长以修复创伤后缺陷。这涉及研究与细胞表面上的AAT相互作用（通常称为受体），并研究相互作用发生后细胞内发生的情况。2。评估AAT对软骨损伤的治疗修复的潜力。我们将使用称为Prolastin-C的批准的AAT产品进行实验，以评估其在再生受损的软骨和骨缺损中的功效。我们的研究将涉及实验室测试以及创伤后骨关节炎的临床前模型3。研究内源性AAT在软骨再生中的作用。在这里，我们将使用基因修饰的小鼠缺乏产生AAT的基因。这些动物是商业上可用且可行的。我们将将它们应用于我们的关节损伤模型，以评估在关节损伤的情况下是否自然发生AAT有助于软骨维持和修复。在完成后，该项目可以将AAT识别为一种新型的疾病改良性骨关节炎药物。由于Prolastin-c（由Grifols产生的血浆AAT）已经用于治疗AAT罕见遗传缺乏症患者的肺部疾病，因此我们认为该项目可以指导该新的治疗剂的快速重新应用试验。总而言之，我们旨在发现AAT影响软骨细胞的机制，并用骨关节炎的人类细胞和动物促进软骨修复。在项目完成和进一步的资金支持下，我们的最终目标是开发基于AAT的药物，这些药物可以减慢骨关节炎的进展，并为患有这种疾病的人提供长期缓解。