Wilkinson Piers, Bozo Ilya Y, Braxton Thomas, Just Peter, Jones Elena, Deev Roman V, Giannoudis Peter V, Feichtinger Georg A
Division of Oral Biology, School of Dentistry, University of Leeds, Leeds, United Kingdom.
CDT Tissue Engineering and Regenerative Medicine, Institute of Medical and Biological Engineering, University of Leeds, Leeds, United Kingdom.
Front Bioeng Biotechnol. 2021 Mar 17;9:626315. doi: 10.3389/fbioe.2021.626315. eCollection 2021.
Bone defects and improper healing of fractures are an increasing public health burden, and there is an unmet clinical need in their successful repair. Gene therapy has been proposed as a possible approach to improve or augment bone healing with the potential to provide true functional regeneration. While large numbers of studies have been performed or in small animal models that support the use of gene therapy for bone repair, these systems do not recapitulate several key features of a critical or complex fracture environment. Larger animal models are therefore a key step on the path to clinical translation of the technology. Herein, the current state of orthopedic gene therapy research in preclinical large animal models was investigated based on performed large animal studies. A summary and an outlook regarding current clinical studies in this sector are provided. It was found that the results found in the current research literature were generally positive but highly methodologically inconsistent, rendering a comparison difficult. Additionally, factors vital for translation have not been thoroughly addressed in these model systems, and the risk of bias was high in all reviewed publications. These limitations directly impact clinical translation of gene therapeutic approaches due to lack of comparability, inability to demonstrate non-inferiority or equivalence compared with current clinical standards, and lack of safety data. This review therefore aims to provide a current overview of ongoing preclinical and clinical work, potential bottlenecks in preclinical studies and for translation, and recommendations to overcome these to enable future deployment of this promising technology to the clinical setting.
骨缺损和骨折愈合不良给公共卫生带来了日益沉重的负担，在其成功修复方面存在尚未满足的临床需求。基因治疗已被提议作为一种可能的方法来改善或促进骨愈合，具有实现真正功能再生的潜力。虽然已经在小动物模型中进行了大量支持基因治疗用于骨修复的研究，但这些模型无法重现严重或复杂骨折环境的几个关键特征。因此，大型动物模型是该技术临床转化道路上的关键一步。在此，基于已开展的大型动物研究，对临床前大型动物模型中骨科基因治疗研究的现状进行了调查。并提供了该领域当前临床研究的总结与展望。结果发现，当前研究文献中的结果总体上是积极的，但在方法上高度不一致，难以进行比较。此外，这些模型系统尚未充分解决对转化至关重要的因素，并且在所有综述的出版物中偏倚风险都很高。由于缺乏可比性、无法证明与当前临床标准相比的非劣效性或等效性以及缺乏安全性数据，这些局限性直接影响了基因治疗方法的临床转化。因此，本综述旨在提供当前正在进行的临床前和临床工作的概述、临床前研究和转化中的潜在瓶颈，以及克服这些问题的建议，以便未来能够将这项有前景的技术应用于临床。
