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

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，导致全球数亿人慢性疼痛和残疾。我们的关节工作，因为有一个特殊的组织层，称为软骨，保持骨骼边缘光滑，避免磨损。如果软骨被创伤事件破坏或被老化和微创伤侵蚀，则会出现以关节功能障碍（缺乏活动性）和剧痛为特征的疾病。在这里，我们重点关注创伤引起的韧带或软骨损伤，这些损伤占全球OA总负担的12%以上：即使采用最佳治疗方法，这些患者中仍有相当一部分（约40%）发生骨关节炎。关节的手术稳定是创伤引起的韧带或软骨损伤的治疗;然而，研究表明，手术稳定后持续的炎症在推动骨关节炎进展方面起着至关重要的作用。因此，我们建议在关节损伤后早期干预减轻炎症和促进软骨修复的因素，可以防止进一步的损伤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，它被称为α 1-抗胰蛋白酶（AAT）。有了这个建议，我们寻求资金，研究基础生物学的AAT在实验创伤后骨关节炎;了解它是如何工作的，可以打开创新的治疗方法，更好地管理骨关节炎。这一假设将通过三个实验目标进行检验。使用人类软骨细胞（产生软骨的细胞）研究AAT的分子机制。我们的目标是揭示AAT如何刺激软骨生长以修复创伤后缺损。这涉及研究AAT与细胞表面对应物（通常称为受体）的相互作用，并研究相互作用发生后细胞内发生的情况。2.评价AAT用于治疗性修复软骨损伤的潜力。我们将使用一种名为Prolastin-C的AAT产品进行实验，以评估其在再生受损软骨和骨缺损方面的功效。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。研究内源性AAT对软骨再生的作用。在这里，我们将使用转基因小鼠，使其缺乏产生AAT的基因。这些动物是可商购的且存活的。我们将把它们应用到我们的关节损伤模型中，以评估在关节损伤的背景下，天然存在的AAT是否以及如何有助于软骨的维护和修复。由于Prolastin-C（血浆AAT，由Grifols生产）已经用于治疗患有AAT罕见遗传缺陷的个体的肺部疾病，我们认为该项目可以指导这种新治疗药物的快速再利用试验。总之，我们的目标是揭示AAT影响软骨细胞和促进软骨修复的机制与人类细胞和动物骨关节炎。项目完成后，在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，可以减缓骨关节炎的进展，并为患有这种疾病的个人提供长期的缓解。