Gene therapies for osteoarthritis: progress and prospects

Anais Defois , Nina Bon , Mathieu Mével , David Deniaud , Yves Maugars , Jérôme Guicheux , Oumeya Adjali , Claire Vinatier
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引用次数: 0

Abstract

Introduction

Osteoarthritis (OA), the most common form of joint disease, affects more than 500 million people worldwide. This painful and debilitating disease imposes a huge socioeconomic cost worldwide. Despite years of promising research, no etiological drug has been successfully introduced into daily clinical practice. In this context, gene therapy (GT) is emerging as a tool capable of meeting an increasingly specialized medical need. Five GT drugs for OA are currently under clinical evaluation, demonstrating the relevance of this tool. However, the widespread use of GT is still limited by considerations of safety, long-term efficacy, controlled and specific targeting, and the presence of neutralizing immune responses. Cartilage, a tissue of interest to target in OA, is a complex tissue to penetrates with the various GT vectors.

Methods

This manuscript reviews current clinical trials involving DNA-based GT for OA and suggests ways to improve recombinant adenoviral and adeno-associated viral vectors, including capsid engineering and transgene sequence optimization to achieve long-term expression of a given transgene exclusively in the target joint tissue, including cartilage.

Results

This review then highlights that the use of hybrid serotypes and/or chemical modifications of capsids are promising for improved tissue targeting. In addition, the choice of promoter and type of vectorized nucleic acid (single- or double-stranded DNA) appears to be critical for efficient transgene expression.

Conclusion

Finally, the combination of increasing knowledge about biocompatible materials and viral vectors should also be a way to improve transduction efficiency, increase the stability of transgene expression, and allow escape from neutralizing antibodies.

骨关节炎的基因疗法:进展与前景
导言骨关节炎(OA)是最常见的关节疾病,影响着全球 5 亿多人。这种令人痛苦和衰弱的疾病在全球造成了巨大的社会经济损失。尽管多年来的研究大有希望,但目前还没有任何病因药物能成功应用于日常临床实践。在这种情况下,基因疗法(GT)正在成为一种能够满足日益专业化的医疗需求的工具。目前,有五种治疗 OA 的基因治疗药物正在接受临床评估,这表明了这一工具的重要性。然而,基因疗法的广泛应用仍受到安全性、长期疗效、可控性和特异性靶向以及中和免疫反应等因素的限制。方法本手稿回顾了目前基于DNA的GT治疗OA的临床试验,并提出了改进重组腺病毒和腺相关病毒载体的方法,包括囊壳工程和转基因序列优化,以实现特定转基因只在包括软骨在内的目标关节组织中长期表达。结果这篇综述强调,使用混合血清型和/或对囊壳进行化学修饰有望改善组织靶向性。此外,启动子和载体核酸类型(单链或双链 DNA)的选择似乎对转基因的高效表达至关重要。结论最后,生物相容性材料和病毒载体方面的知识不断增加,这两者的结合也应成为提高转导效率、增加转基因表达稳定性和摆脱中和抗体的一种方法。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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