Modulating Reactive Astrocytes after Spinal Cord Injury using Emerging Gene Therapy with Transcription Factors

Abstract: Spinal cord injury (SCI) leads to severe and often permanent loss of motor and sensory function due to primary tissue damage followed by secondary processes such as inflammation, oxidative stress, and apoptosis. A major barrier to repair is the glial scar, where reactive astrocytes and chondroitin sulfate proteoglycans (CSPGs) restrict axon regrowth. Rather than removing the scar, new strategies aim to reprogramming reactive astrocytes into functional neurons using transcription factors. This review highlights two recent approaches: NeuroD1-mediated reprogramming, which reduced scar-forming astrocytes, generated mature neurons, and improved locomotor recovery in mouse models; and Ngn2-mediated reprogramming, which converted astrocytes into excitatory glutamatergic neurons with demonstrated functional activity. Together, these findings suggest that astrocyte-to-neuron conversion represents a promising, cell-intrinsic approach to spinal cord repair. Although challenges remain, such as ensuring stability, specificity, and long-term integration, emerging gene therapy with transcription factors may open new possibilities for SCI recovery.