Promising drug against Huntington's disease enters broad study: Shots

Scientists are preparing a large study to determine if a drug can silence the gene that causes a devastating disease called Huntington's disease.

This development follows the discovery that the experimental drug has reduced levels of the damaged protein that causes this devastating disease. The new study will determine if this drug can also stop the progression of the disease.

This is also another sign that drugs built with DNA, or its cellular collaborator RNA, can be powerful tools for fighting diseases that seemed until now out of reach.

Huntington's disease is an interesting target because it is caused by a single mutated gene. It's also a scary and devastating disease.

Symptoms "are like having Alzheimer's, Parkinson's and ALS [Lou Gehrig’s disease] at the same time, when the situation is in full swing, "said Jeanette Garcia, a 57-year-old lawyer in San Jose, California.

If one of your parents has Huntington's disease, there is a 50% chance that you will contract the disease. In the United States, about 30,000 people carry the deadly gene.

Garcia and his nine siblings lost their mothers because of the disease. They know the terrible chances. When they gather for family reunions and the discussions turn to Huntington, "it's suddenly this terrifying prospect that we all face," she says.

Garcia decided to undergo genetic testing for this disease in 2008 and discovered that she had inherited the damaged gene. She recently saw the first signs of the disease, including involuntary movements, which she noticed while watching a video of herself, "and I went," Shit whore, OK here we go. "

But his illness is appearing at a time that could be happy. She goes to a neurologist to see if she could benefit from a study that elicits a lot of excitement.

Last year, Roche's drug company Genentech said an experimental drug dramatically reduced the amount of disease-inducing protein measured in the cerebrospinal fluid. The results of this study, involving 46 patients, were published on Monday by the New England Journal of Medicine.

The protein is not fully eliminated with the experimental drug, but animal experiments suggest that a significant reduction in this protein might be enough to calm the symptoms.

The researchers are about to launch a clinical trial involving 660 volunteers with early symptoms of the disease, to determine if the drug, called RG6042, can slow down or stop Huntington's progression.

"It's so exciting," says Garcia. "I want to be 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 stray gene that causes the disease by carefully studying families in an area of ​​Venezuela where the disease is almost epidemic.

His discovery is one of the very great successes of researching the genes of the disease. But it took all the intervening years to develop this promising angle of attack.

A significant advance has been the development of methods to silence a damaged gene. Thus, cells do not convert these erroneous instructions into dangerous proteins, such as those that cause Huntington's symptoms.

Scientists have devised several methods to scramble this signal. The drug Roche uses a piece of custom-built genetic material called the antisense oligonucleotide to block the process. Other advanced research projects targeting Huntington and other diseases use a technique called RNA interference to achieve a similar result.

Another major challenge has been determining how to introduce the drug into the brain. Scientists at Ionis Pharmaceuticals in San Diego have figured out how to achieve this with the antisense oligonucleotide targeting Huntington's syndrome.

The answer has proven to be injecting it into the cerebrospinal fluid, which flows up and down the spine and into the brain. "The drug could actually be transferred quite easily to the brain and then enter the target brain tissue," says Dr. Scott Schobel, head of research on this drug at Roche, who co-develops the experimental drug with Ionis.

Roche began recruiting patients for this study in January, but stopped the trial to reshape it after discovering that the drug did not need to be injected as often as expected.

"We will resume our activities over the next few weeks, if not months," said Schobel.

The study is supposed to follow patients for 25 months, which should leave enough time to determine if symptoms are controlled by treatment.

George Yohrling, a scientist at the Huntington's Disease Society of America, says his main concern is whether the experimental drug will penetrate deep enough into the brain to stop the disease.

Otherwise, he says that other treatments under development could succeed in this regard. One of the strategies is to use viruses to administer one of these gene-inhibiting drugs.

"Many different approaches are being developed at different stages of drug discovery around the world," Yohrling said. "It's really very exciting."

This evolution follows more than 20 years of enthusiasm for gene mutagen strategies.

"At first, there was wild enthusiasm," says Dr. Judy Lieberman, a professor of pediatrics at Harvard Medical School. "There were literally hundreds of biotechnology companies trained to do it."

But they soon came up against technical and scientific obstacles, and almost all of them gave up these efforts.

As scientists tried to solve these problems, Huntington's disease appeared to be an attractive target, although it was a rare disease with a much smaller potential market than, for example, Alzheimer.

The first antisense oligonucleotide approved by the Food and Drug Administration as a drug treats an even rarer condition, called spinal muscular atrophy. And there are now competitive products targeting this disease, in part because of the financial incentives that pharmaceutical companies have to develop drugs for "orphan" diseases. (The drugs are also extremely expensive).

Drug developers are also aware that this strategy could be helpful for common disorders, such as high cholesterol. This is an active area for drug development.

Pharmaceutical companies would seize the opportunity to develop a drug for Alzheimer's or autism, Yohrling said, if only they could identify a single target gene to disrupt. This strategy "now makes the drug" unbearable, "he says.

But it's getting ahead. Even before the FDA plans to approve a treatment for Huntington, Roche will have to demonstrate that its experimental drug is safe and effective.

Garcia is eager to help them make their point, joining the study if she can, and encouraging others to do the same. She says that she can not even let herself hope that the treatment will work for her. She thinks of her four children and six grandchildren.

She has a grandson who was born blind and who is also at risk for Huntington, she says. "I'm just not going to stop because I do not want him to be forced to handle that."

You can contact NPR Scientific Correspondent Richard Harris at [email protected].