PTEN deletion in spinal pathways via retrograde transduction with AAV-RG enhances forelimb motor recovery after cervical spinal cord injury; Sex differences and late-onset pathophysiologies

Spinal cord injuries (SCI) cause permanent functional impairments by disrupting motor and sensory pathways. Axon regeneration is limited due to adult neurons' lack of growth capacity and inhibitory factors, particularly at the injury site. However, regeneration can be stimulated by deleting phosphatase and tensin homolog (PTEN) in spinal pathway origin cells. We used a retrogradely transported AAV variant (AAV-rg) to deliver gene-modifying cargos to these cells, aiming to enhance motor function recovery. PTENf/f;RosatdTomato and control mice received varying doses of AAV-rg/Cre after a C5 dorsal hemisection injury. Grip strength in forelimbs was measured using a grip strength meter. PTENf/f;RosatdTomato mice treated with AAV-rg/Cre showed significant improvements in gripping ability compared to controls, with males recovering more than females. However, 5–7 weeks post-injury, many treated mice began displaying pathophysiological symptoms, including excessive scratching and hindlimb rigidity, which worsened over time. Our findings indicate that AAV-rg/Cre injections can improve forelimb recovery after SCI, but late-onset functional abnormalities arise under these experimental conditions, with underlying mechanisms yet to be explored.