C286, an orally available retinoic acid receptor β agonist drug, regulates multiple pathways to achieve spinal cord injury repair

Front. Mol. Neurosci., 2024 · DOI: 10.3389/fnmol.2024.1411384 · Published: August 20, 2024

Spinal Cord Injury Pharmacology Neurology

Simple Explanation

This research focuses on a new drug, C286, that targets a specific receptor (RARβ) to help repair spinal cord injuries. It works by influencing multiple pathways involved in nerve regeneration. The drug was tested in rats with spinal cord injuries, showing improvements in nerve regeneration and reduced tissue damage. C286 also showed promise in human cells, suggesting it could be effective in people. C286 also demonstrated target engagement at the lesion site in nerve-injured rats and in healthy human participants. Further, C286 increased neurite density and an increase in the number of synapses.

Study Duration

4 weeks

Participants

Male Sprague–Dawley rats and healthy human participants

Evidence Level

Level 1: Preclinical and Phase 1 clinical trial

Key Findings

1
C286 upregulates tenascin-C, integrin-α9, and osteopontin in the injured spinal cord, promoting nerve regeneration.
2
In a spinal cord contusion model, C286 reduces inflammation and tissue loss, improving locomotor function.
3
C286 engages its target receptor RARβ2 in white blood cells in humans, correlating with increased doses.

Research Summary

This study introduces C286, an oral RARβ agonist, as a potential therapy for spinal cord injuries. It demonstrates that C286 modulates gene expression and ECM molecules to promote tissue repair and axonal regeneration. Preclinical trials in rats with sensory root avulsion and spinal cord contusion showed significant functional recovery. C286 reduced inflammation, tissue loss, and promoted chondroitin sulphate proteoglycan clearance. The study also confirmed target engagement of C286 in humans and identified S100B as a potential biomarker for regeneration. These findings support further clinical testing of C286.

Practical Implications

Therapeutic Potential

C286 could offer a new therapeutic avenue for spinal cord injuries and other neurodegenerative conditions.

Clinical Translation

The drug's oral availability and target engagement in humans make it a promising candidate for clinical trials.

Biomarker Identification

S100B can potentially be used to monitor regeneration progress in patients treated with C286.

Study Limitations

1
The analysis represents a snapshot of transcriptional and protein expression after 4 weeks, lacking earlier time point data.
2
The rat model studies were conducted only in males, potentially limiting generalizability to females.
3
The study acknowledges that further research is needed to fully understand the sequential pathways regulating regeneration.

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