Can Germ-Killer Slay Genetic Disease?
Can an old germ-killer provide a new weapon against genetic disease?
Some researchers battling such diseases as cystic fibrosis, muscular dystrophy and hemophilia hope so.
Intrigued by a handful of preliminary studies, they are giving the antibiotic gentamicin to carefully selected patients suffering from those conditions.
The weird thing is that nobody is asking gentamicin to kill germs. Rather, scientists hope to show that the drug can counteract the genetic defects that made those patients sick. And if that's true, scientists say, it could signal a new treatment strategy that goes far beyond those three diseases.
"I'm most excited when I think about the general potential," said Dr. Steve Sommer of the City of Hope National Medical Center in Duarte, Calif., who has begun the hemophilia study.
"In theory, it can work for any (genetic) disease."
Gentamicin has been used for more than 30 years in the United States. It's generally given to treat a variety of infections, including those of the urinary tract or dangerous blood infections called sepsis in newborns.
When it comes to genetic disease, scientists already know that gentamicin and other drugs that act like it can't be a cure-all. That's because the kind of defect gentamicin targets shows up in only a fraction of people with a given genetic disease.
It's too soon to tell if the approach will really help anybody, and experts caution that patients should not try it on their own. For one thing, gentamicin use runs the risk of side effects like hearing loss and kidney damage.
But scientists hope the medicine will lead them to more benign drugs that have the same effect. It might inspire research that finds drugs that work against other kinds of mutations. And in the meantime, some say, the old antibiotic itself might help the right patients.
In the new studies:
People with cystic fibrosis suffer from persistent coughing and potentially fatal lung infections. Scientists hope that eventually, drugs like gentamicin will aid lung functioning in patients, helping them lead healthier, longer lives. Some 5 percent to 10 percent of cystic fibrosis patients in general — but the majority of patients of Ashkenazi Jewish descent — have the kind of defect gentamicin targets.
Duchenne sufferers also lack a key protein, and the result is muscles that waste and weaken. A preschooler may have trouble climbing stairs or running; most patients lose their ability to walk by age 12. Gentamicin probably couldn't restore walking ability because so much muscle would have been lost already. So doctors would want to use it early in the disease.
Up to 15 percent of Duchenne patients have the kind of mutation that might yield to gentamicin.
Patients with the bleeding disorder can lead relatively normal lives now by injecting a genetically engineered replacement protein, but Sommer hopes the gentamicin work could lead to a pill instead. And for developing countries, where the replacement protein is prohibitively expensive, Sommer said, even injected gentamicin offers the hope of an affordable drug that could save children who now die.
The class of mutation targeted by gentamicin appears in about 10 percent of patients with the most common kind of hemophilia, and about 30 percent of severe cases of the less common kind. Sommer's work is supported by grants from the National Hemophilia Foundation and the federal government.
With the new studies, scientists hope to strengthen the case that gentamicin and other "aminoglycoside" antibiotics can treat genetic disease by helping patients produce key proteins. Normally, patients with a particular kind of genetic defect make only incomplete proteins, and the drugs are expected to encourage their bodies to finish the job. Such drugs wouldn't lead to normal levels of protein, but for many diseases, even a limited amount can help.
Scientists have known for decades that antibiotics like gentamicin can counter this kind of genetic defect in yeast cells. But it wasn't until 1996 that David Bedwell, a microbiologist at the University of Alabama at Birmingham, and his colleagues demonstrated the effect in human cells with a mutated cystic fibrosis gene.
And in 1999, H. Lee Sweeney at the University of Pennsylvania School of Medicine showed the same result in mice that couldn't ordinarily make dystrophin, the protein lacking in Duchenne muscular dystrophy. With treatment, the mice made enough dystrophin to protect their muscles.
Sweeney's paper galvanized efforts to look at antibiotics for genetic diseases, says one researcher in the field, Michael Howard of the University of Utah.
"I think seeing it in a living organism like a mouse made it much more dramatic and much more believable that it might work," he said.
Already, the search for better drugs has shown some promise, said Sweeney, who's working with PTC Therapeutics in South Plainfield, N.J.
"We actually have a few that look more promising than gentamicin at this point," he said. In the next year or two, one might be ready for studies in people, he said.
So far, previous research with gentamicin in patients has been very limited and preliminary.
In muscular dystrophy, two small studies found no direct sign of dystrophin production but did find evidence suggesting that muscle damage from the disease was reduced.
Dr. Jerry Mendell, a neurologist at Ohio State who led one of the studies, is launching the new follow-up with support from the Muscular Dystrophy Association and the federal government. He suspects both prior studies may have overlooked a real increase in dystrophin production.
In cystic fibrosis, two researchers who found encouraging signs in preliminary studies of the nose are following up. Dr. J.P. Clancy, a colleague of Bedwell's at Birmingham, is leading a bigger study with support from the Cystic Fibrosis Foundation. And Dr. Michael Wilschanski of the Shaare Zedek Medical Center in Jersualem, is continuing work as well.
"I see great promise in this avenue of research," Wilschanski said.
He said he gets e-mails regularly from around the world, from parents of cystic fibrosis patients, asking how the research is progressing.
That "tells me I have to keep going," Wilschanski said.