Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, Canada.
Osteoarthritis Cartilage. 2024 Apr;32(4):372-384. doi: 10.1016/j.joca.2023.12.009. Epub 2024 Jan 8.
Significant advances have been made in our understanding of osteoarthritis (OA) pathogenesis; however, no disease-modifying therapies have been identified. This review will summarize the gene therapy landscape, its initial successes for OA, and possible challenges using recent studies and examples of gene therapies in clinical trials.
This narrative review has three major sections: 1) vector systems for OA gene therapy, 2) current and emerging targets for OA gene therapy, and 3) considerations and future directions.
Gene therapy is the strategy by which nucleic acids are delivered to treat and reverse disease progression. Specificity and prolonged expression of these nucleic acids are achieved by manipulating promoters, genes, and vector systems. Certain vector systems also allow for the development of combinatorial nucleic acid strategies that can be delivered in a single intraarticular injection - an approach likely required to treat the complexity of OA pathogenesis. Several viral and non-viral vector-based gene therapies are in clinical trials for OA, and many more are being evaluated in the preclinical arena.
In a post-coronavirus disease 2019 (COVID-19) era, the future of gene therapy for OA is certainly promising; however, the majority of preclinical validation continues to focus heavily on post-traumatic models and changes in only cartilage and subchondral bone. To ensure successful translation, new candidates in the preclinical arena should be examined against all joint tissues as well as pain using diverse models of injury-, obesity-, and age-induced disease. Lastly, consideration must be given to strategies for repeat administration and the cost of treatment owing to the chronic nature of OA.
我们对骨关节炎（OA）发病机制的理解已经取得了重大进展；然而，尚未发现能够改变疾病进程的治疗方法。本综述将总结基因治疗的现状、其在 OA 中的初步成功，以及使用最近的研究和临床试验中基因治疗的实例来探讨可能面临的挑战。
这篇叙述性综述分为三个主要部分：1）用于 OA 基因治疗的载体系统，2）OA 基因治疗的当前和新兴靶点，3）考虑因素和未来方向。
基因治疗是通过递送来治疗和逆转疾病进展的核酸策略。通过操纵启动子、基因和载体系统，可以实现这些核酸的特异性和长期表达。某些载体系统还允许开发组合核酸策略，可以通过单次关节内注射来递送，这是治疗 OA 发病机制复杂性所需的方法。几种基于病毒和非病毒载体的基因治疗正在进行 OA 的临床试验，还有更多的正在临床前领域进行评估。
在后 COVID-19 时代，OA 的基因治疗的未来无疑是有希望的；然而，大多数临床前验证仍然严重侧重于创伤后模型，并且仅改变软骨和软骨下骨。为了确保成功转化，临床前领域的新候选物应该在使用多种损伤、肥胖和年龄诱导疾病的模型的情况下，针对所有关节组织以及疼痛进行检查。最后，由于 OA 的慢性性质，必须考虑重复给药的策略和治疗成本。
