Thiorphan reprograms neurons to promote functional recovery after spinal cord injury
We previously identified an embryonic shift in the corticospinal motor neuronal transcriptome after spinal cord injury associated with successful axonal regeneration<sup>1</sup>. 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<sup>2</sup>, 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.
Authors
- E Rosenzweig (ORCID: https://orcid.org/0000-0002-0370-9643)
- Paul Pavlidis (ORCID: https://orcid.org/0000-0002-0426-5028)
- B. Ogan Mancarci (ORCID: https://orcid.org/0000-0002-1452-0889)
- Michael J. Castle (ORCID: https://orcid.org/0000-0001-7566-6454)
- Adam R. Ferguson (ORCID: https://orcid.org/0000-0001-7102-1608)
- Kimberly M. Groeniger (ORCID: https://orcid.org/0000-0002-7315-1403)
- Alexander A. Khalessi (ORCID: https://orcid.org/0000-0002-5559-9175)
- T. A. Riley
- Daniel Kulinich (ORCID: https://orcid.org/0000-0003-3744-5110)
- Erna A. van Niekerk (ORCID: https://orcid.org/0000-0001-5233-1432)
- Eleni Sinopoulou (ORCID: https://orcid.org/0000-0002-5196-8615)
- Najla Kfoury (ORCID: https://orcid.org/0000-0001-6693-2976)
- J. Russell Huie (ORCID: https://orcid.org/0000-0001-5594-4277)
- Mark H. Tuszynski (ORCID: https://orcid.org/0000-0003-4182-1481)
- Riki Kawaguchi (ORCID: https://orcid.org/0000-0002-2489-4825)
- Tamara Vokes (ORCID: https://orcid.org/0000-0003-1628-9673)
- Camila Marques Freria (ORCID: https://orcid.org/0000-0002-3171-8141)
- Shinpei Okawa (ORCID: https://orcid.org/0000-0001-8888-8128)
Institutions
- San Francisco VA Medical Center (US)
- United States Department of Veterans Affairs (US)
- University of California, Los Angeles (US)
- University of Pittsburgh (US)
- University of California, San Francisco (US)
- UC San Diego Health System (US)
- University of California San Diego (US)
- Michael Smith Health Research BC (CA)
- Neurological Surgery (US)
Publication Details
- Journal
- Nature
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1038/s41586-025-09647-y
- Citations
- 5
- Primary Topic
- Nerve injury and regeneration
- Type
- article
- Field-Weighted Citation Impact
- 4.55