Low Dose NeuroD1 Delivery in Mouse TBI Models

Traumatic brain injury (TBI) often results in serious neuronal tissue damage that can lead to progressive neurological impairment. NeuroD1, a transcription factor involved in neuronal differentiation, may be able to facilitate recovery post-TBI through the promotion of both neuroprotection and astrocyte-to-neuron reprogramming. The efficacy and optimal parameters for NeuroD1-based treatment, however, remain uncertain. This study investigated the effects of AAV-mediated NeuroD1 delivery in TBI mouse models, focusing on cellular reprogramming at low dosages. Dose response experiments revealed that lower viral doses provided the greatest transduction specificity. Notably, lower viral titers resulted in greater astrocyte-specific transduction whereas higher titers increased transduction in off-targets (neurons), potentially due to toxicity and/or leakage. Using these low dosages, our findings indicate that NeuroD1 treatment did not produce statistically significant structural restoration, nor did it greatly alter neuroinflammation measures; however, it did allow for functional improvement in beam walk performance, suggesting enhanced neurological recovery. Prospective studies should refine experimental conditions, incorporate a broader range of behavioral assessments, and explore combination therapies to enhance both functional and structural recovery. NeuroD1-based interventions remain a promising avenue for promoting functional improvement following TBI, although further research is required to drive these findings to clinical applications.