Thiorphan reprograms neurons to promote functional recovery after spinal cord injury
- E. A. van Niekerk
- C. Marques de Freria
- B. O. Mancarci
- K. Groeniger
- D. Kulinich
- T. Riley
- R. Kawaguchi
- S. Okawa
- T. Vokes
- E. S. Rosenzweig
- E. Sinopoulou
- M. J. Castle
- R. Huie
- A. R. Ferguson
- N. Kfoury-Beaumont
- A. Khalessi
- P. Pavlidis
- M. H. Tuszynski
2025-10-29
We previously identified an embryonic shift in the corticospinal motor neuronal transcriptome after spinal cord injury associated with successful axonal regeneration 1 . 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 screen 2 , 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.