Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain

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 FOXF1 to the degenerated IVD in an in vivo model. Injured IVDs treated with eEVs loaded with FOXF1 demonstrated robust sex-specific reductions in pain behaviors compared to control groups. Furthermore, significant restoration of IVD structure and function in animals treated with FOXF1 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. [Display omitted] •Non-viral gene therapy using FOXF1 engineered extracellular vesicles (FOXF1 eEVs) for intervertebral disc (IVD) degeneration.•FOXF1 eEVs reprogram diseased IVD cells to a healthy state evidenced by structure/function restoration & pain alleviation.•Sex-specific differences in pain behavior are present in a mouse model of discogenic back pain and with treatment.•FOXF1 restores IVD disc height, tissue hydration, proteoglycan, and conserves mechanical properties.