Thiorphan reprograms neurons to promote functional recovery after spinal cord injury

• 成果类型: Article
• 署名作者: van Niekerk, E. A.; de Freria, C. Marques; Mancarci, B. O.; Groeniger, K.; Kulinich, D.; Riley, T.; Kawaguchi, R.; Okawa, S.; Vokes, T.; Rosenzweig, E. S.; Sinopoulou, E.; Castle, M. J.; Huie, R.; Ferguson, A. R.; Kfoury-Beaumont, N.; Khalessi, A.; Pavlidis, P.; Tuszynski, M. H.
• 署名单位: University of California System; University of California San Diego; University of British Columbia; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; Pennsylvania Commonwealth System of Higher Education (PCSHE); University of Pittsburgh; University of California System; University of California San Francisco; US Department of Veterans Affairs; Veterans Health Administration (VHA); San Francisco VA Medical Center; University of California System; University of California San Diego; US Department of Veterans Affairs; Veterans Health Administration (VHA)
• 刊物名称: NATURE
• ISSN/ISSBN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-025-09647-y
• 发表日期: 2025-12-11
• 页码: 410462
• 关键词: STEM-CELL GRAFTS; GROWTH; connectivity

摘要

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.