By Mahua Sarkar and Diana Shu-Lian Chow
“Each day we deal with patients and families desperately searching for answers to spinal cord injury.” These words (PDF) by Susan Howley, executive vice president for research at the Christopher Reeve Foundation, give us a peek into the current therapeutic insufficiency for spinal cord injury (SCI).
SCI is a devastating neurological condition that severely impacts physical and psychological health, independence, and quality of life of an SCI patient, and also affects his/her family, friends, and society at large. Most recent statistics indicate that almost 12,500 new cases (PDF) of SCI (both tetraplegic and paraplegic) are reported every year, and currently about 450,000 people are affected by SCI in North America. The financial burden imposed by SCI in North America exceeds nine billion dollars annually.
The pathophysiology of spinal cord injury is complex but has been gradually better characterized to the molecular and cellular levels. Labs with extensive research around the globe are putting forward their best efforts to find a cure. However, to date no therapy is available that improves functional recovery following SCI. There is a dire need for therapeutic treatment options.
The long term goal of SCI research is to identify neuroprotective agents based on sound scientific rationale, targeting multiple mechanisms that are activated during the acute phase of SCI. Literature search indicates that several preclinical and clinical trials have explored the efficacy of individual drugs, hormones, monoclonal antibodies, and cell transplantation in SCI, but only a few showed modest positive outcomes with the single agent. Therefore, a combination therapy of drugs with potentially additive or synergistic neuroprotective/regenerative effects is a rational approach for further research.
One of the lead and promising candidates possessing neuroprotective activity is riluzole, a Food and Drug Administration (FDA) approved drug for the treatment of ALS. The phase 1 clinical trial was a success and indicated that riluzole is well tolerated and promising for patients with cervical injuries to achieve higher motor scores and more robust conversions of motor impairment grades to higher grades than a matched untreated group of patients. It is currently being investigated in the phase 2 clinical trials for efficacy in SCI, led by Robert Grossman, M.D., neurosurgeon and principal investigator of North American Clinical Trials Network (NACTN) for SCI.
As part of the ongoing research, our lab is involved in evaluating pharmacokinetics of the combination of riluzole with other pharmacologic agents for enhancing riluzole availability at the site of action. The choice of an appropriate combination is most crucial for a promising treatment. In this case, riluzole was selected for its promising pharmacological action. However, riluzole is also known as a substrate of efflux transporter at the blood-brain barrier, which may lead to insufficient bioavailability in the spinal cord. Therefore, a combination of riluzole and another FDA approved neuroprotective agent (targeting alternate mechanisms) and also a transporter inhibitor was selected. We have achieved some positive preliminary results and hope that this combination can be translated from the preclinical to clinical arena, and eventually become a potential therapeutic option.
I am grateful to be a part of this research and optimistic that any scientific contribution I make will move the research forward and hopefully ultimately provide a therapeutic solution to the eagerly waiting patients with SCI. Part of the research will be presented at the forthcoming 2015 AAPS Annual meeting and Exposition in Orlando, Florida.