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

Chronic low back pain, often stemming from intervertebral disc (IVD) degeneration, plagues millions worldwide, contributing to both personal suffering and economic strain. Despite the prevalence of this condition and its role in the opioid crisis, effective interventions that address both structural damage and symptomatic pain are sorely lacking. However, a groundbreaking study by researchers at The Ohio State University offers hope in the form of a novel non-viral gene therapy approach utilizing engineered extracellular vesicles (eEVs) to target the underlying causes of discogenic back pain (DBP).

In this pioneering research, the scientists developed a cutting-edge technique to deliver the developmental transcription factor FOXF1 directly to degenerated IVDs in an in vivo model. FOXF1 is known for its critical role in tissue development and regeneration, making it a promising candidate for addressing the structural deficits associated with DBP. By harnessing the power of eEVs, tiny membrane-bound particles secreted by cells, the researchers were able to efficiently transport FOXF1 to the site of injury without the need for viral vectors.

Study Design: Overview of the study methods describing
the surgery groups, eEV injections, and evaluated dependent variables

(1) Primary mouse embryonic fibroblasts (PMEFs) were transfected via electroporation with pCMV6 or FOXF1 plasmids followed by engineered extracellular vesicle (eEV) isolation. (2) Surgery was performed on 15-week-old male and female wild type mice (N = 11–12 per experimental group, N = 5–6 per sex), where non-injury controls were animals that underwent surgical exposure of IVD with no puncture, injured animals sustained IVD puncture with saline injection, and pCMV6 eEV and FOXF1 eEVs treated animals received a single injection of eEVs, respectively in the L4/L5, L5/L6, and L6/S1 Vertebrae. Micrograph (right panel) highlighting IVDs (black arrows) within the surgical field. (3) Pain behavioral assessments were conducted throughout 12 weeks post operation and treatment, with assessment of function and structure at 12 weeks with magnetic resonance imaging (MRI), micro computed tomography (μCT/microCT), mechanical tests, Alcian blue/picrosirius red staining (AB/PSR), Dimethyl Methylene Assay (DMMB), and immunohistochemistry (IHC).

The results of the study were nothing short of remarkable. Animals treated with eEVs loaded with FOXF1 exhibited significant reductions in pain behaviors compared to control groups, demonstrating the therapeutic potential of this innovative approach. Moreover, structural improvements in the treated IVDs were evident, with notable increases in disc height, tissue hydration, proteoglycan content, and mechanical properties observed. These findings mark the first successful attempt to simultaneously address tissue degeneration and pain in an animal model of DBP using eEV-based non-viral gene delivery.

The implications of this research extend far beyond DBP. By demonstrating the efficacy of eEV-mediated gene therapy in alleviating both pain and structural damage, this study opens the door to new treatment possibilities for a wide range of painful musculoskeletal disorders. From osteoarthritis to tendon injuries, the potential applications of this technology are vast and promising.

While further research is needed to refine and optimize this approach for clinical use, the findings represent a significant step forward in the quest to combat chronic pain and restore tissue function. With continued innovation and collaboration, non-viral gene therapy using eEVs could revolutionize the field of regenerative medicine, offering hope to millions suffering from debilitating musculoskeletal conditions.

Tang SN, Salazar-Puerta AI, Heimann MK et al. (2024) Engineered extracellular vesicle-based gene therapy for the treatment of discogenic back pain. Biomaterials [Epub ahead of print]. [article]

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