BioProject

Retinoic acid receptor beta (RARbeta) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal mode of action. More...

Retinoic acid receptor beta (RARbeta) is an emerging therapeutic target for spinal cord injuries (SCIs) with a unique multimodal mode of action. We have developed a first in class RARbeta 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. Protein expression analysis showed that C286 upregulates tenascin-C, integrin alpha9 and osteopontin in the injured cord. We further demonstrate the drug's efficacy in a rodent model of spinal cord contusion where it remodulates ECM molecules, hampers inflammation and prevents tissue loss. Treatment with the agonist induced upregulation of RARbeta in dorsal root and spinal neurons. In the single ascending dose (SAD) cohorts in white blood cells from healthy human participants RARbeta2 expression increases with dose and at the highest dose administered the pharmacokinetics are similar to doses used in rat proof of concept (POC) studies. 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 RARbeta selective showed these were ineffective in aiding regain of function in avulsed rats. Taken together our data suggests that further clinical testing of C286 in POC trials is justifiable for a broad spectrum of SCIs Overall design: To study the mechanisms driving nervous injury repair driven by the RAR-beta agonist C286, Sensory root avulsion model in rats has been used. Briefly, animals were treated with vehicle or C286 igand in absence or in presence of spinal root avulsion injuries. Spinal cord samples were microdissected and used for RNA extraction analysed by next generation sequencing. Less...