The final, formatted version of the article will be published soon.
ORIGINAL RESEARCH article
Front. Mol. Neurosci.
Sec. Molecular Signalling and Pathways
Volume 17 - 2024 |
doi: 10.3389/fnmol.2024.1411384
This article is part of the Research Topic The role of retinoic acid signaling in maintenance and regeneration of the CNS: from mechanisms to therapeutic targeting View all 4 articles
C286 an orally available retinoic acid receptor agonist drug regulates multiple pathways to achieve spinal cord injury repair
Provisionally accepted- 1 King's College London, London, United Kingdom
- 2 INSERM UMR8030 Génomique Métabolique du Genoscope, Evry, Île-de-France, France
- 3 Cardiff University, Cardiff, United Kingdom
- 4 University of Surrey, Guildford, South East England, United Kingdom
- 5 Richmond Pharmacology Ltd., London, United Kingdom
Retinoic acid receptor (RAR) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal mode of action. We have developed a first in class RAR agonist drug, C286, with demonstrated safety in a Phase 1 trial and proven efficacy in a sensory root avulsion rat model. Using genome-wide and pathway enrichment analysis in spinal cords of avulsed rats we show that C286 modulates regenerative pathways amongst which extracellular matrix (ECM) and adhesion molecules were of note. We further demonstrate the drug's efficacy in a rodent model of spinal cord contusion where it regulates the same pathways. Importantly, target engagement was demonstrated in humans, where a proportional increase of RAR2 expression in white blood cells was observed with increasing drug exposure and that treatment with C286 of human iPSC-derived neurons results in a significant increase in neurite outgrowth. We also show plasma S100B in nerve injured rats as a correlative measure of axonal regeneration. Finally, comparison with other clinically available retinoids which are non RAR selective showed these were ineffective in aiding regain of function in avulsed rats.Taken together our data suggests that C286 signalling in neurite/axonal outgrowth is conserved between species and between different nerve injuries suggesting that further clinical testing of C286 in POC trials is justifiable for a broad spectrum of neurodegenerative conditions.
Keywords: Retinoic acid, drug, pathway analysis, nerve regeneration and repair, human data
Received: 02 Apr 2024; Accepted: 29 Jul 2024.
Copyright: © 2024 Goncalves, wu, Clarke, Grist, Moehlin, MENDOZA-PARRA, Hobbs, Kalindjian, Fok, Mander, Hassanin, Bendel, Täubel, Mant, Carlstedt, Jack and Corcoran. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Jonathan Corcoran, King's College London, London, United Kingdom
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.