Painful musculoskeletal disorders such as intervertebral disc (IVD) degeneration associated with chronic low back pain (termed “Discogenic back pain”, DBP), are a significant socio-economic burden worldwide and contribute to the growing opioid crisis. Yet there are very few if any successful interventions that can restore the tissue's structure and function while also addressing the symptomatic pain. Here we have developed a novel non-viral gene therapy, using engineered extracellular vesicles (eEVs) to deliver the developmental transcription factor to the degenerated IVD in an model. Injured IVDs treated with eEVs loaded with demonstrated robust sex-specific reductions in pain behaviors compared to control groups. Furthermore, significant restoration of IVD structure and function in animals treated with eEVs were observed, with significant increases in disc height, tissue hydration, proteoglycan content, and mechanical properties. This is the first study to successfully restore tissue function while modulating pain behaviors in an animal model of DBP using eEV-based non-viral delivery of transcription factor genes. Such a strategy can be readily translated to other painful musculoskeletal disorders.

中文翻译：

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基于工程细胞外囊泡的基因疗法用于治疗椎间盘源性背痛

与慢性腰痛（称为“椎间盘源性背痛”，DBP）相关的椎间盘（IVD）退变等疼痛性肌肉骨骼疾病是全世界重大的社会经济负担，并导致日益严重的阿片类药物危机。然而，很少有成功的干预措施能够恢复组织的结构和功能，同时还能解决症状性疼痛。在这里，我们开发了一种新型非病毒基因疗法，使用工程细胞外囊泡（eEV）将发育转录因子传递到模型中退化的 IVD 中。与对照组相比，用 eEV 治疗的受伤 IVD 表现出明显的性别特异性疼痛行为减少。此外，观察到接受 eEV 治疗的动物 IVD 结构和功能显着恢复，椎间盘高度、组织水合作用、蛋白聚糖含量和机械性能显着增加。这是第一项使用基于 eEV 的转录因子基因非病毒传递在 DBP 动物模型中成功恢复组织功能同时调节疼痛行为的研究。这种策略可以很容易地转化为其他痛苦的肌肉骨骼疾病。