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Emerging Therapies for Spinal Cord Injury

Michael Fehling
Michael Fehling
Spinal cord injury (SCI) remains a daunting challenge for clinicians and scientists alike, but progress is being made. Dr. Michael Fehlings has made major contributions to this field, recognized with last year's Lister Prize, the highest award for academic achievement in the Department of Surgery. With hundreds of peer reviewed clinical and basic science contributions, Dr. Fehlings has made significant contributions to the field over the course of his distinguished career. Over the last two decades, the prognosis for patients with spinal cord injury has improved appreciably: cervical SCI had a mortality rate of 40% in the early 1980s, but current critical care techniques have reduced this to approximately 5%. Progress in improving the neurological disability that these patients face has been much slower.

Years of research strongly suggest that SCI may be amenable to therapy. The MRI era has shown us clearly that even in the absence of spinal cord function, the spinal cord is very rarely transected. This raises the possibility of enhancing or restoring function in the remaining neural tissue. We have learned that a significant proportion of the damage that occurs following SCI occurs in delayed fashion. A complex series of inter-related "secondary injury" events occur on the cellular level leading to progressive loss of spinal cord cells and axons. Secondary injury results from processes such as ischemia, mitochondrial dysfunction, toxicity from excitatory amino acid release and dysregulation of electrolytes. The delayed nature of these events provides a window which may be therapeutically exploitable.

A number of pharmacological agents which specifically target these processes have entered human SCI clinical trials. Within the last decade, human trials demonstrated modest benefit from the administration of GM-1 ganglioside (also known as Sygen®), thyrotropin releasing hormone and methylprednisolone. Only methylprednisolone has come to clinical use, however its use has become controversial because of concern that its side-effects may outweight its benefits. We are currently without an effective, widely accepted therapy for SCI treatment.

Appreciable research in this field is beginning to bear fruit, however. A new generation of putative therapies are making their way to the clinical realm, leading to new-found optimism for SCI researchers and patients alike. One of the earliest therapies Dr. Fehlings studied in his research laboratory is the pharmacological agent riluzole, which antagonizes cellular sodium entry and release of the excitotoxic neurotransmitter glutamate. In work which earned him a gold medal from the Royal College of Physicians and Surgeons of Canada, Dr. Fehlings and his team demonstrated a reduction in spinal cord damage as well as improvement in functional outcome when experimental animals were treated with this agent. Phase I clinical trials will begin in 2008 and we hope that the same benefits will be seen in humans.

Recent years have seen the Fehlings laboratory explore a number of other promising therapeutic strategies. Gene therapy with VEGF, which stimulates angiogenesis, is showing benefit in pre-clinical studies. His laboratory has shown that their viral delivery technique leads to an increase in spinal cord vascularity with a reduction in apoptotic cell loss.

The Fas death receptor is a trigger of apoptotic cell loss. Work by the Fehlings group with an agent which blocks this receptor has demonstrated a 30% decrease in cell death following SCI as well as improved functional outcome. This may be a promising therapy in the future.

Dr. Fehlings' group has also has great success with so-called cell-replacement therapy in the subacute injury phase. Their protocol involves isolation of neural precursor cells from the mouse, and subsequent transplantation into peri-lesional rat spinal cord. Co-administration of a growth factor cocktail is then used to drive these cells to a predominant oligodendroglial differentiation. Many axons remain intact following SCI, but are dysfunctional because of oligodendroglial loss and demyelination. Remarkably these exogenous cells have demonstrated the capacity to remyelinate these demyelinated but viable axons leading to improved electrophysiology and functional recovery.

Another noteworthy SCI therapy which Dr. Fehlings has helped bring to clinical trials is Cethrin®, which is a promising pharmaceutical agent developed by Dr. Lisa McKerracher from McGill. While myelin is normally essential for facilitating axonal conduction, it becomes inhibitory to axonal outgrowth following trauma when such sprouting might be beneficial. While a number of inhibitory molecules exist, they have all been demonstrated to signal via a common intracellular pathway, specifically the proteins Rho and Rho kinase. Cethrin® potently inhibits Rho activation and can be applied transdurally at the time of a decompressive surgery shortly after injury. This promising agent is currently being investigated in early-stage clinical trials.

All of these approaches are years away from widespread clinical use, in the best case scenario. It would be even better if we could alter existing management practices in SCI care to facilitate improved outcome with measures currently within our means. Many have postulated that early decompression of the spinal cord may be such a measure, which could lead to better outcomes; indeed, animal studies have shown definitively that early decompression is of benefit. The utility of early decompression is much less clear in the human polytrauma patient who is frequently medically unstable in the early hours and days following an SCI. Michael Fehlings has worked with his mentor Charles Tator to initiate the Surgical Trial in Acute Spinal Cord Injury Study (STASCIS) which aims to answer this important question. This trial, which has been changed to a prospective cohort study because of slow accrual under randomized methodology, uses the 24h post-injury mark to mark the boundary between early and late surgery. With over 240 patients enrolled, this trial will soon be complete. Early analysis suggests a treatment effect, and there is thus a strong chance that this study will alter the surgical management of this condition.

Any one of these contributions to SCI research would be remarkable; it is astounding that Dr. Fehlings has contributed so significantly to the development of so many of the emerging therapies for SCI. Though he started his career in General Surgery, Alan Hudson recognized his talent when he recruited him to a career in Neurosurgery... and one can't help but wonder how the SCI field would be different had this recruitment been unsuccessful. Michael Fehlings has become one of the world's foremost neurosurgeons and SCI researchers and we look forward to the advancements that he will bring in the years to come.

Gregory Hawryluk
Neurosurgery Resident




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