We previously identified an embryonic shift in the corticospinal motor neuronal transcriptome after spinal cord injury associated with successful axonal regeneration1. Exploiting this transcriptional regenerative ‘signature’, here we used in silico screens to identify small molecules that generate similar shifts in the transcriptome, and identified thiorphan—a neutral endopeptidase inhibitor—as a lead candidate. In a new adult motor cortex neuronal in vitro screen2, thiorphan increased neurite outgrowth 1.8-fold (P < 0.001). We then infused thiorphan into the central nervous system beginning 2 weeks after severe C5 spinal cord contusions and, when combined with a neural stem cell graft, thiorphan elicited significant improvements in forelimb function (P < 0.005) and corticospinal regeneration (P < 0.05). Extending clinical relevance, thiorphan significantly increased neurite outgrowth in primary cortical neuronal cultures from a 56-year-old human. These findings represent a new path for drug discovery, starting from in silico screens to proof-of-concept in adult human brain cultures.
