Treatment of spinal cord injury, by restoration of neuronal networks using a combination of surgery and KCL-286, an orally available retinoic acid receptor β drug

The most complicated nerve injuries occur in the spinal nerves. Following traumatic injury at the nerve root attachment to the spinal cord (avulsion), there is degeneration of nerve fibres in the root and spinal cord. The result for the patient is paralysis with sensory loss and typical excruciating severe pain. An obvious fundamental surgical treatment for such injuries is to re-create continuity for the ruptured spinal nerve and the roots detached from the spinal cord. Reimplanting motor spinal roots leads to neuronal growth within the spinal cord and distally in the peripheral nerves, resulting in recovery of shoulder and proximal arm muscles. Sensory function cannot be restored surgically from dorsal root to spinal cord replantation due to the impediment of regrowing sensory fibres at the spinal cord glial scar<i>.</i> However, when a ganglionectomised dorsal root-in effect a peripheral nerve conduit-is implanted into the spinal cord sensory system, intramedullary (secondary) sensory neurons extend distally, resulting in recovery of some sensory function. Patients have profited from this surgery with better functional performance without movement synkinesis and reduced pain. Full functional restoration after a nerve injury cannot be achieved by means of surgery alone due to the impediment of regrowing sensory fibres at the spinal cord glial scar. Embryonic axogenesis was studied to identify pathways required for adult spinal cord injury repair. From this, a key regulator, the retinoic acid receptor β, was identified. This signalling cascade can be reactivated in the injured adult nervous system with the orally available drug KCL-286. This drug has been shown to be safe and tolerated in humans at doses predicted to be used in human spinal cord injuries to provide functional recovery. Therefore, the combination of surgical root implantation and KCL-286 represents a promising therapeutic strategy to improve the quality of life for patients with root avulsions and the broader population of patients with spinal cord injuries.