Despite various available treatments, highly prevalent osteoarthritis (OA) cannot be cured in patients. In light of evidence showing mitochondria dysfunction during the disease progression, our goal was to develop a novel therapeutic concept based on the transplantation of mitochondria as a platform to deliver recombinant adeno-associated virus (rAAV) gene vectors with potency for OA. For the first time, to our best knowledge, we report the successful creation of a safe mitochondria/rAAV system effectively promoting the overexpression of a candidate insulin-like growth factor I (IGF-I) by administration to autologous human osteoarthritic articular chondrocytes versus control conditions (reporter mitochondria/rAAV lacZ system, rAAV-free system, absence of mitochondria transplantation; up to 8.4-fold difference). The candidate mitochondria/rAAV IGF-I system significantly improved key activities in the transplanted cells (proliferation/survival, extracellular matrix production, mitochondria functions) relative to the control conditions (up to a 9.5-fold difference), including when provided in a pluronic F127 (PF127) hydrogel for reinforced delivery (up to a 5.9-fold difference). Such effects were accompanied by increased levels of cartilage-specific SOX9 and Mfn-1 (mitochondria fusion) and decreased levels of Drp-1 (mitochondria fission) and proinflammatory tumor necrosis factor alpha (TNF-α; up to 4.5-fold difference). This study shows the potential of combining the use of mitochondria with rAAV as a promising approach for human OA.

中文翻译：

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线粒体/rAAV IGF-I 平台在人骨关节炎关节软骨细胞中的自体移植治疗骨关节炎


尽管有各种可用的治疗方法，但高度普遍的骨关节炎 （OA） 无法治愈患者。鉴于证据表明疾病进展过程中线粒体功能障碍，我们的目标是开发一种基于线粒体移植的新型治疗概念，作为递送对 OA 有效的重组腺相关病毒 （rAAV） 基因载体的平台。据我们所知，我们首次报告了通过施用自体人骨关节炎关节软骨细胞与对照条件（报告线粒体/rAAV lacZ 系统，无 rAAV 系统，无线粒体移植;高达 8.4 倍差异）成功创建安全的线粒体/rAAV 系统，有效促进候选胰岛素样生长因子 I （IGF-I） 的过表达。相对于对照条件，候选线粒体/rAAV IGF-I 系统显着改善了移植细胞中的关键活性（增殖/存活、细胞外基质产生、线粒体功能）（差异高达 9.5 倍），包括在用于增强递送的 pluronic F127 （PF127） 水凝胶中提供时（高达 5.9 倍差异）。这些影响伴随着软骨特异性 SOX9 和 Mfn-1 （线粒体融合） 水平的增加以及 Drp-1 （线粒体裂变）和促炎性肿瘤坏死因子 α （TNF-α;差异高达 4.5 倍）水平降低。这项研究表明了将线粒体与 rAAV 结合使用作为人类 OA 的有前途的方法的潜力。