Gene Therapy Postpones Lou Gehrig's Disease Symptoms
La Jolla, CA – A unique gene therapy method postpones the symptoms and nearly doubles the life span in a mouse animal model of Lou Gehrig's disease, a research team led by the Salk Institute has found.
The findings are the first to show this degree of recovery after the paralyzing and ultimately fatal nervous system disorder begins and may lead eventually to a new, gene-based treatment for the disease that affects more than 30,000 Americans. The study appears in the August 8 issue of the journal Science.
Fred H. Gage, professor of genetics, Salk research fellow Brian Kaspar, Jeffrey Rothstein, professor of neurology at Johns Hopkins University, and their colleagues found that injecting a gene that produces the nerve cell growth-stimulating protein, insulin like growth factor-1 (IGF-1), into muscles resulted in longer life spans, preserved nerve cells and reduced muscle wasting.
Lou Gehrig's disease, known as amyotrophic lateral sclerosis (ALS), is marked by the degradation of nerve cells that control muscle movement. It quickly attacks these motor nerve cells in the brain and spinal cord, resulting eventually in total paralysis and death. Its cause is unknown. While the disease was first identified in the 19th century, it gained international attention in 1939 when baseball great Lou Gehrig announced he had ALS and retired from the New York Yankees. He died two years later.
"IGF-1 protein has been used in clinical trials for a while, with marginal results," said Gage. "The biggest challenge has been to deliver the protein across the blood-brain barrier into the central nervous system. By injecting our viral vector into muscles, the gene could then deliver the protein into nerve cells that controlled the muscle, resulting in the preservation of those nerve cells that would otherwise have succumbed more quickly to ALS."
"ALS is a terrible disease, and patients have few choices for therapy today," said Rothstein, also professor of neuroscience and director of the Robert Packard Center for ALS Research at Johns Hopkins. "This animal study is the first to identify a treatment that slows the disease once symptoms have already appeared, a significant finding that offers insight into the disease mechanism and important therapeutic potential."
Gage and his colleagues found that delivery of a non-toxic gene therapy, using an adeno-associated virus that carried IGF-1 into muscle (with subsequent transfer of IGF-1 to neurons dying in ALS), delayed disease onset by 31 days and expanded the mice's life span to a maximum of 265 days, compared to 140 days for the untreated mice. IGF-1 was also able to extend life spans by 22 days when injected after symptoms appeared, indicating the method's potential treatment for different stages of disease. In addition to extending survival, treatment with the gene therapy maintained physical movement for a significantly longer time than in untreated mice and provided 20 percent more muscle mass.
The researchers demonstrated that IGF-1 triggers a molecular pathway that appears to preserve motor nerve function. When the receptor for IGF-1 is activated, an enzyme called Akt has a phosphate molecule added to it (a process called phosphorylation). The Akt enzyme is activated and helps block the process of apoptosis, or programmed cell death.
"IGF-1 has been known to increase the number of phosphorylated Akt molecules, which inhibits apoptosis by directly inhibiting different pro-apoptotic signals," said Gage. "We found that IGF-1 decreased levels of a specific protein involved in apoptosis by more than 63 percent compared to untreated mice. Understanding this pathway led us to experiment with IGF-1 in the first place, and underscores the vital importance of understanding the fundamental mechanisms of cellular function to medical advances."
While this research is still in the experimental animal stage and a number of steps need to be taken before any possible therapy is deemed safe and effective enough for use, researchers are in the planning stages of human trials for this gene therapy method.
This research was supported by grants from Project ALS, Christopher Reeve Paralysis Foundation, the National Institute on Aging and the National Institute of Neurological Diseases and Stroke.
The Salk Institute for Biological Studies, located in La Jolla, Calif., is an independent nonprofit organization dedicated to fundamental discoveries in the life sciences, the improvement of human health and conditions, and the training of future generations of researchers. Jonas Salk, M.D., founded the institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes Birth Defects Foundation.