AAV-9 based therapies for recovery of locomotion in mouse models of spinal cord injury

Introduction: Spinal cord injury (SCI) results in long-term functional deficits due to both axonal damage and neuronal loss. We describe the delivery of novel neurotrophic factors via AAV9-based intravenous injections, drug X and drug Y, which selectively target spinal cord lesions with the goal of improving functional recovery in experimental SCI models.

Methods: Forty adult mice underwent T8 spinal cord crush injuries and treated with control vector (n=9), vehicle vector (n=9), drug X (n=11) or drug Y (n=11). In order to objectively assess locomotor recovery, we used DeepLabCut software to track 22 key points on the body of the mice, generating 136 gait-related metrics describing the locomotion of the mouse. These metrics describe the angle, height, and distance of the tracked points at different stages of the gait cycle. Principal component analysis (PCA) of these metrics identified bodyweight support (PC1, 32.1% of variance) and movement speed (PC2, 12.7% of variance) as the primary indicators of recovery from injury.

Results: In comparing locomotor recovery at baseline, 1 week (1w), and 8 weeks (8w) post-SCI across different treatment groups we found that by 8 weeks, treatment groups had significantly improved hindlimb height (correlated with PC1) compared to controls. However, at 1 week post-SCI, these same groups exhibited a dragging phenomenon, where body weight support was sacrificed for increased total speed of locomotion by depending primarily on the forelimbs in the acute phase of injury. This pattern suggests that early in recovery, murine SCI models seem to prioritize speed over stability, but over time, treatments with neurotrophic factors can lead to long-term improvements in body support and hindlimb function.

Conclusion : These findings highlight the potential of AAV9-based therapies delivering neurotrophic factors targeting mechanisms of neuroprotection and neurorecovery post-SCI, demonstrating their promise for enhancing long-term functional outcomes. Future research will focus on further characterizing the safety and efficacy of these treatments employing data-driven metrics for assessing recovery.