Scientists are gearing up a major study to find out whether a drug can silence the gene that causes a devastating illness called Huntington's disease.
This development follows the discovery that the experimental drug reduced levels of the damaged protein that causes this mind-robbing ailment. The new study will determine whether that drug can also stop progression of the disease.
It is also another sign that drugs built with DNA, or its cellular collaborator RNA, can be powerful tools for tempering diseases that until now have seemed out of reach.
Huntington's disease is an apt target because it's caused by a single mutated gene. It also a frightening and devastating disease.
The symptoms "are like having Alzheimer's, Parkinson's and ALS [Lou Gehrig's disease] simultaneously, when it's in full swing," says Jeanette Garcia, a 57-year-old advocate in San Jose, Calif.
If one of your parents has Huntington's disease, there's a 50-50 chance you will get it, too. About 30,000 people in the United States carry the deadly gene.
Garcia and her nine siblings lost their mother to the disease. They know the terrible odds. When they get together for family reunions and talk turns to Huntington's, "it is all of a sudden this terrifying prospect we're all faced with," she says.
Garcia decided to take the genetic test for this condition in 2008 and found out she had inherited the damaged gene. She's recently been seeing the first signs of the illness, including involuntary movements, which she noticed when watching a video of herself, "and I went, 'Holy crap, OK here we go.' "
But her disease is emerging at what could be a fortunate moment. She's heading off to a neurologist to see if she would qualify for a study that is generating a lot of excitement.
Last year, drugmaker Roche's Genentech unit said that an experimental drug sharply reduced the amount of illness-inducing protein measured in people's spinal fluid. The results of that study, involving 46 patients, were published Monday by the New England Journal of Medicine.
The protein isn't eliminated entirely with the experimental drug, but animal experiments suggest that reducing it significantly could be enough to stave off symptoms.
The researchers are now about to launch a trial involving 660 volunteers with early symptoms of the disease, to see if the drug, called RG6042, can slow or stop Huntington's progression.
"It's so exciting," Garcia says. "I want to be a part of it."
This study marks a milestone for Huntington's disease. More than 25 years ago, a scientist named Nancy Wexler was able to identify the errant gene that causes the disease by painstakingly studying families in a region of Venezuela where the disease is nearly epidemic.
Her finding was one of the early, great successes in tracking down disease genes. But it has taken all the intervening years to develop this promising angle of attack.
One huge advance has been the development of methods to silence a damaged gene, so cells don't convert those errant instructions into dangerous proteins, such as the one that causes the symptoms of Huntington's.
Scientists have developed several methods to jam this signal. The Roche drug uses a custom-built piece of genetic material called an antisense oligonucleotide to block the process. Other advanced research projects aimed at Huntington's and other diseases use a technique called RNA interference to accomplish a similar result.
Another major challenge has been to figure out how to get the drug into the brain. Scientists at Ionis Pharmaceuticals in San Diego figured out how to make that happen with the antisense oligonucleotide targeting Huntington's.
The answer turned out to be injecting it into spinal fluid, which circulates up and down the spine and into the brain. "The drug could actually transfer quite readily to the brain and then sink into the target brain tissue," says Dr. Scott Schobel, who heads the research effort on this drug at Roche, which is co-developing the experimental drug with Ionis.
Roche started recruiting patients for this study in January, but halted the trial to redesign it, after discovering the drug didn't need to be injected as often as they had planned.
"We're going to get back up and running over the next several weeks to months," Schobel says.
The study is supposed to follow patients for 25 months, which should be enough time to determine whether people's symptoms are held in check by the treatment.
George Yohrling, a scientist at the Huntington's Disease Society of America, says his main concern is whether the experimental drug will penetrate deeply enough into the brain to stop the disease.
If not, he says other treatments under development could succeed in that regard. One strategy is to use viruses to deliver one of these gene-silencing drugs.
"A lot of different approaches are being worked on in different stages of drug discovery across the world," Yohrling says. "It's really quite exciting."
This development follows more than 20 years of boom-and-bust excitement about gene-silencing strategies.
"Initially there was wild enthusiasm," says Dr. Judy Lieberman, a professor of pediatrics at Harvard Medical School. "There were literally hundreds of biotech companies formed to do that."
But they quickly hit technical and scientific roadblocks, she says, "and eventually almost all of them about abandoned these efforts."
As scientists gradually worked their way through these challenges, Huntington's disease emerged as an appealing target, despite being a rare disease with a far smaller potential market than, for example, a drug for Alzheimer's disease.
The first antisense oligonucleotide to be approved as a drug by the Food and Drug Administration treats an even rarer condition, called spinal muscular atrophy. And there are now competitive products targeting that disease, thanks in part to the financial incentives drug companies get to develop drugs for "orphan" diseases. (The drugs are also extraordinarily expensive).
Drug developers are also aware that this strategy could be useful for common disorders, such as high cholesterol. That's an active area for drug development.
Drug companies would jump on an opportunity to develop a drug for Alzheimer's or autism, Yohrling says, if only they could identify a straightforward target gene to disrupt. That strategy "now makes the 'undruggable' druggable," he says.
But that's getting ahead of the story. Before the FDA even considers approving a treatment for Huntington's, Roche will have to demonstrate that its experimental drug is safe and effective.
Garcia is eager to help them make that case, by joining the study if she can, and encouraging others to do the same. She says she can't even let herself hope that the treatment will work for her. She's thinking of her four children and six grandchildren.
She has a grandson who was born blind and is also at risk for Huntington's, she says. "I'm just not going to stop because I don't want him to have to deal with this."
You can contact NPR Science Correspondent Richard Harris atrharris@npr.org.
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