Columbia researchers have participated in a new study that points toward a potential treatment for amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
The study, led by Dr. Robert M. Friedlander of Harvard Medical School and the Brigham and Women's Hospital Neuroapoptosis Laboratory and Neurosurgical Service, will be published in the April 14 issue of Science. Dr. Serge Przedborski, an associate professor of neurology and pathology in Columbia's College of Physicians & Surgeons, was the main collaborator in the study that also involved researchers from the University of Chicago's Department of Medicine.
The study employed mice genetically engineered to have a mutation in the superoxide dismutase-1 gene (SOD-1), the same mutation found in the familial or hereditary form of ALS. Caspases are enzymes that are unleashed in apoptosis, or planned cell death, to destroy cells that are no longer needed or are abnormal. Researchers believe that in neurodegenerative diseases like ALS, the process of caspase-mediated apoptosis is misdirected and begins to destroy neurons.
In the study, mice given a compound called zVAD-fmk that blocks the action of caspases developed ALS-like symptoms later and lived 22 percent longer than the mice who did not receive the drug.
Dr. Przedborski points out that while zVAD-fmk inhibits several caspases at once, pharmaceutical companies have compounds under development that may inhibit caspases more specifically. He calls the study "proof of principle" that a caspase-inhibiting drug could help delay onset of symptoms and prolong life in ALS patients.
Currently, no treatment exists for ALS. "Virtually all our patients are dying," Dr. Przedborski says. "We can prolong life with mechanical ventilation, we can temporarily improve their quality of life with different strategies, but ultimately our patients are dying."
Dr. Przedborski notes that caspase inhibitors would not be a miracle drug and would not cure ALS. However, he suggests that a "cocktail" of drugs that attack the neurodegenerative process at several different points--similar to the successful strategy now used to treat HIV infection--could one day be used to slow the development of symptoms and prolong survival in ALS patients.
"Our study results are promising as they provide a foundation for evaluating drugs that could slow down the progression of ALS," says Dr. Friedlander, senior author of the study. "Although much more research needs to be conducted in this area, our research does bring us one step closer to finding a treatment for this tragic disease."
ALS is characterized by progressive loss of the motor neurons in the brain, brainstem, and spinal cord. On average, people who develop ALS die within five years of contracting the disease. Roughly 10 percent to 20 percent of ALS cases are hereditary.
All of the mice in the study were implanted with osmotic pumps that delivered zVAD-fmk, or a placebo, into the ventricles of the brain. They received the pumps at 60 days old, when the symptoms of the disease had not yet appeared, and received zVAD-fmk or placebo continuously for 56 days. The motor function of the mice was measured by timing how long they were able to stay on a rotating treadmill-like device called a Rotarod at a certain speed. The mice who received the highest doses of zVAD-fmk survived for an average of 153 days, as compared with 126 days for their untreated littermates, and were symptom-free for 20 days longer, on average.
The research was funded by the National Institute for Neurological Disorders and Stroke, the Muscular Dystrophy Association, the ALS Association, and Project ALS.