Despite various available treatments, highly prevalent osteoarthritis 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 platforms to deliver recombinant adeno-associated viral (rAAV) gene vectors with a potency for osteoarthritis. 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 9.5-fold difference), including when provided in a PF127 hydrogel for reinforced delivery (up to 5.9-fold difference). Such effects were accompanied with increased levels of cartilage-specific SOX9 and Mfn-1 (mitochondria fusion) and with decreased levels of Drp-1 (mitochondria fission) and proinflammatory 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：

---

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作为人骨关节炎的新型治疗概念。


尽管有多种可用的治疗方法，但患者无法治愈高度普遍的骨关节炎。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治疗概念作为平台，以提供对骨关节炎具有效力的重组腺相关病毒 （rAAV） 基因载体。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、无线粒体移植）成功创建安全线粒体/rAAV 系统有效促进候选胰岛素样生长因子 I （IGF-I） 的过表达（差异高达 8.4 倍）。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 PF127 水凝胶中提供用于增强递送时（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 TNF-α 水平的降低 （差异高达 4.5 倍）。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。