Scientists say they may be on the threshold of a new treatment for Lou Gehrig's disease, reporting today that a novel gene therapy nearly doubled the life span of mice afflicted with the fatal, nerve-wasting disease.
Researchers at the Johns Hopkins University and the Salk Institute in La Jolla, Calif., said the treatment caused the mice to bulk up and slowed the destruction of nerve cells - called motor neurons - that control practically all movement, including breathing.
But the scientists were equally excited about the way the treatment works - through simple, one-time injections into weakened muscles. Once there, viral particles armed with protective genes migrate to the neurons in a spinal cord and brain that are under attack.
This could remove a major stumbling block on the road to treating amyotrophic lateral sclerosis, a devastating ailment that afflicts 30,000 Americans. It could deliver a treatment to the central nervous system without performing risky surgery or injecting anything into sensitive nerve centers.
"I think this is a significant breakthrough," said Dr. Marinos C. Dalakas, chief of the neuromuscular disease branch at the National Institutes of Health.
"The key thing to me is the way they have found the means for delivering these [protective] factors to the motor neurons. You can easily give these injections to the muscles that have been weak, and target the areas of the spinal cord that have been affected."
Results of the study appear in today's issue of the journal Science. The experiment was led by Fred H. Gage and Brian Kaspar at the Salk Institute and Dr. Jeffrey D. Rothstein at the Johns Hopkins School of Medicine.
Rothstein, a neurologist who heads a large research team at Hopkins, says a clinical trial involving humans could begin within a year. The trial, requiring government approval, would be conducted at Hopkins and possibly Harvard University.
Not a cure alone
Doctors treating humans might inject the virus into muscles throughout the body, including those in the arms, legs and trunk as well as others in the throat that control swallowing and speech.
Scientists in the study cautioned that the therapy alone is not a potential cure because it does not reverse the cell death that paralyzes and eventually kills victims. It also remains to be seen how powerfully the treatment acts in humans.
But ultimately, said Rothstein, the best therapy might be a "cocktail" that combines this type of treatment with other therapies aimed at reversing the disease. He and others hope to find a way to harness stem cells to replace dying nerve cells.
ALS, the disease associated with Gehrig, the New York Yankees first baseman who succumbed in 1941, kills most of its victims within two to five years after symptoms appear. Victims lose the ability to lift a hand, walk, swallow or speak. Death usually comes when the muscles that control breathing shut down.
In a cruel twist, the disease affects the neurons, but not the mind itself, so victims remain knowing witnesses to their decline. Doctors diagnose about 5,000 cases of the disease each year in the United States.
The therapeutic substance is a gene that serves as a factory for insulin growth factor-1, a protein that interferes with cell death. Scientists inserted copies of the gene into an adeno-associated virus. This is a noninfectious particle which, they noticed, can travel from muscles to the motor neurons that trigger them.
The protein had been injected into animal and human muscle before, with little effect. But in those cases, it had no way to cross the blood-brain barrier. In the latest attempt, the virus provides a stealthy path to the neurons.
In the mouse experiment, scientists injected the viral package into muscles in the hind legs and in the chest. The chest muscles were important targets because they power the lungs.
Mice that received the gene therapy at 60 days of age developed symptoms of Gehrig's disease at 152 days - 31 days later than the untreated mice. On average, they also lived 40 days longer. The treated mouse that survived the longest lived 265 days, compared with 140 days for the untreated mouse.
"It's a new way to deliver therapies to ALS patients, and looks to be quite potent," Rothstein said.
Mice used in the experiment were manipulated to carry a human gene that triggers the wasting disease. The rodents are often used to test therapies because diseases occur faster in their compressed lives, and are easily observed by scientists.
According to Gage, the virus carried the genes right into the affected nerve cells. Once there, the genes not only protected the cells from within, but also secreted growth factor into the surrounding tissue.
"This is best therapy we've ever seen in mice," said Rothstein, who cautioned that better therapies would probably emerge as research progresses. Though it is impossible to say whether the gene therapy will succeed in humans, scientists hope it will prove better than the drug Rilutek, which adds only a few months of survival. In mouse studies, that drug increased survival by only 14 days.
The research was funded, in large part, by Project ALS, a New York nonprofit organization founded by Jenifer Estess, a former theater producer who suffers from the disease, and her sisters.
"We haven't put it into people but we're thrilled about what it's doing for animals," said Valerie Estess, who has recruited many of the scientists involved in funded research. "The clinical applications seem within reach."