“I'm ecstatic,” said Nancy Wexler, who in 1993 identified the mutation. “Huntington's is horrible, one of the worst diseases known to mankind, and certain death. . . . We know it’s a bad gene, making a bad protein, that makes people sick, that kills your brain cells. Anything that could impact that, we knew that that could be a cure.”
The research, supported by Ionis Pharmaceuticals in Carlsbad, Calif., was conducted by scientists at more than half a dozen locations in Europe and Canada. This international team collaborated to create IONIS-HTTRx, the first drug to directly target the cause of Huntington's.
The Huntington's gene sends instructions via RNA for cells to create a protein. In people with the mutation, the protein is a toxic form that kills nerve cells and damages the brain. The new drug works by delivering a small piece of genetic material that sticks to the RNA and prevents it from building proteins.
The early phase clinical trial involved three dozen subjects with the disease and was conducted to establish the safety and tolerability of IONIS-HTTRx. It did that, and it also showed that the drug dramatically curtailed the nerve-cell-killing protein, with larger reductions at successively higher doses for all the subjects. There were no reported side effects.
On Monday, Ionis was awarded a $45 million license fee from its commercial partner, Roche, which will now manage all future studies.
Huntington's was first described in 1872 by 22-year-old American physician George Huntington. The pernicious, hereditary disease usually starts causing symptoms between ages 30 and 50 and progresses over a period of one to two decades until it proves fatal. One of the early physical signs is involuntary tremors. The death of certain brain cells most vulnerable to the disease renders a person unable to walk, talk or reason, although she retains the ability to understand language and recognize friends and family.
Patients and doctors often say Huntington's is like having Alzheimer's disease, amyotrophic lateral sclerosis and Parkinson's disease -- all at the same time. Around 30,000 people in the United States have symptoms of Huntington's, and many more people have the mutation and will develop the disease. Children of people with the mutated gene have a 50 percent chance of inheriting it.
The development of a genetic test for the disease in 1994 allowed children of a parent with Huntington's to know whether they will eventually come down with the disease. Between 7 and 9 percent choose to find out, according to the National Institutes of Health.
“When people get tested, there's nothing we can give them. Zero,” Wexler, who is also the president of the Hereditary Disease Foundation, said. “You can't give them hope, you can't give them medicine. If this therapy can reverse or prevent it, the minute people get the test, we can immediately give them this drug before they get sick.”
Those with Huntington's or at risk of the disease have been waiting a long time for a breakthrough.
“I was so thrilled to have something, such a dramatic treatment,” said 44-year-old Christopher O'Brien, who is in the middle stages of the disease. “This is the most exciting thing ever, being a patient.”
O'Brien lives in Rochester, N.Y., and has a medical degree and PhD. He was hoping to study Huntington's, which killed his mother when he was a child. But in 2000, in the middle of his residency at Baylor University Medical Center in Texas, he had trouble passing his neurology boards no matter how hard he studied. Suspecting his cognitive problems were an early sign of Huntington's, he tested himself, then sent a blood sample to a lab to confirm the results. O'Brien had the mutated gene, which would also take the lives of two sisters.
Important progress in identifying the gene came from Wexler's study of a village in Venezuela where she and a team of researchers, over the past four decades, have identified 18,149 individuals with Huntington's spanning 10 generations. These Venezuelan kindreds (related families sharing a common ancestor) make up the world’s largest genetically-related Huntington's disease community.
Researchers think that this new method of targeting the central cause of Huntington's might have application in the treatment and perhaps eventual cure of other neurodegenerative diseases, including potentially some forms of Alzheimer's, ALS and Parkinson's. Those diseases are more complicated, and involve multiple genes, but the idea of “silencing” mutant genes is an approach they think will be widely explored.
The good news for Huntington's patients is the hope that the drug might even reverse the progression of the disease.
“What's really interesting in animal studies, if you stop the production of the mutant protein, not only does progression stop, but the brain starts to heal itself,” said Christopher Ross, director of the Huntington's Disease Center at Johns Hopkins Medicine, who was not involved in the research. “Which means there might be improvement.”
As insidious as Huntington's disease is medically, it is psychologically complex and emotionally fraught for affected families.
Meghan Donaldson, 50, is the CEO of the Hereditary Disease Foundation, which has been intimately involved in pushing research forward. She is also one of O'Brien's six siblings. She chose to be tested at age 28 because she had lived with the specter of Huntington's her entire life. She does not carry the mutant gene.
“I was 6 when my mother was diagnosed,” she said. “I don’t know if there was a time when I didn’t know I was at risk. . . . I grew up thinking the worst, that I would get it in my 30s, so I knew I had to live my life now.”
When Donaldson found out she did not carry the mutant gene, she felt gratitude and relief.
“I rolled the genetic dice and I won,” she said.
Blair Leavitt, a researcher at the University of British Columbia and the lead investigator for the North American group that conducted the study, said: “This is the culmination of 20 years of work for all of us. To see that result and to know what it means -- it means we've taken a really good promising step.”
Leavitt expects the phase 3 clinical trial to start next year and that in three years, they might be able to establish proof of the drug's effectiveness.
“I think we’re at the end of the beginning and the start of the end,” he said. “This approach is going to make a difference in the very near future.”