Despite advances in treatment for a multitude of neurological conditions such as multiple sclerosis and Parkinson’s disease, Huntington’s disease remains incurable. This relatively rare genetic disease is often diagnosed in midlife and progresses to eventual death. However, several promising new developments have offered a ray of hope to Huntington’s patients, their at-risk children, and the clinicians who treat them.
Roughly 25,000 individuals in the United States have Huntington’s disease, according to Christopher Ross, MD, PhD, professor of psychiatry and neuroscience at Johns Hopkins University School of Medicine. “There are probably on the order of another 75,000 people who are already at risk,” he told Rare Disease Report ®
The disease occurs because of a gene mutation known as a CAG triplet repeat expansion, in which a specific gene sequence mistakenly repeats over and over. “What seems to happen is when you get this expanded chain of polyglutamine, that region changes its structure,” said Dr Ross. “When you have a repeated stretch of DNA like that, it’s unstable. That abnormal protein interacts with other abnormal proteins in the cell.”
Having a long stretch of abnormal DNA segments invariably leads to a diagnosis of Huntington’s disease. However, not all of these gene chains are the same length in all people. Someone with 38 CAG repeats, for example, might see the disease manifest much later in life than someone with 48 CAG repeats. Access to this information can provide crucial clues that can help guide treatment.
For those at risk of Huntington’s disease who undergo gene testing, knowing the length of their DNA chain means having a much better idea of when the condition will present itself. “For increasing numbers of people now getting tested, we can predict approximately when they’re going to get the disease,” Dr Ross said. “We can study changes in the brain before we diagnose symptoms of the disease.”
Probably the best known of Huntington’s disease symptoms is chorea, or involuntary movement. However, the disease manifests in other ways, in the form of cognitive and memory problems or conditions such as anxiety and depression. “Basically, [these] can get worse over time in a number of patients, and they become disabled from exacerbation of these problems,” said Burton Lasater Scott, MD, PhD, a professor of neurology at Duke University Medical School in Durham, North Carolina. While current medications can help control chorea, he said, “existing medications don’t do anything for suppression of the illness.”
That all may be about to change.
Making waves in the scientific community is the idea of using certain drugs to treat Huntington’s disease that were developed to treat other ailments. Several years ago, a team led by Duke University neurologist Al La Spada, MD, PhD, found that the drug KD3010—which researchers had hoped would be used as a diabetes treatment but which never was approved for that use—showed promise for Huntington’s disease when tested in mice and on human neurons created from stem cells. The drug worked on a transcription factor known as PPAR Delta, which is expressed in the brain and has a role in mitochondrial function. “We repurposed the drug when we found it could cross the blood-brain barrier,” Dr La Spada said.
A newer study led by Dr La Spada found that the cancer drug bexarotene enabled mice who had a Huntington’s disease-like affliction to move more easily, recover from brain deterioration, and live longer. “The 2 studies together suggest that if you can come up with a nice molecule to activate PPAR Delta and get it across the blood-brain barrier, it should be an effective therapy for Huntington’s disease,” he said. Dr La Spada feels that KD3010 would be superior to bexarotene for use in treating Huntington’s disease, but “in an ideal world, we would combine bexarotene and KD3010 and give them both together. Then you wouldn’t have to give as high a dose.”
Several companies currently are developing PPAR Delta agonists that might be used against the disease. “I’m confident that we will get a PPAR Delta agonist into human Huntington’s disease patients in the next several years,” Dr La Spada said, although which agonist remains unknown. He also envisions PPAR Delta therapy treating more than just the neurological symptoms of Huntington’s disease and would like to see it address the cognitive problems and metabolic issues that cause muscle atrophy and wasting.
Another development generating excitement is a new type of enzyme being used in the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing system, allowing for greater specificity as scientists look to silence the defective gene responsible for Huntington’s disease. As such, a group of Polish researchers has been working on editing cells from Huntington’s patients using the CRISPR technology, which is only a few years old. According to a press release, the team was able to remove the troublesome DNA without disturbing other essential DNA, and the process appeared to be safe and without sequence-specific side effects.
Immunotherapy is also a promising area for the treatment of Huntington’s disease. Vaccinex, a Rochester, New York-based biotechnology company, is in the process of conducting an ongoing study known as the SIGNAL trial. This double-blind trial is looking at the role of an antibody known as VX15, which affects an inflammatory molecule called semaphorin 4D, which experts believe plays a role in the disease. In the first phase of the trial, known as Cohort A, 36 patients were randomized and given either VX15 or a placebo for 6 months. All participants then received VX-15 for 5 months. All of the subjects had brain imaging performed at the beginning of the study, and then again at 6 and 11 months. The results showed that being treated with VX15 enabled subjects to avoid some of the progressive changes to the brain shown in the control group and which are hallmarks of Huntington’s disease.
In a previous article published in Rare Disease Report®,
George Yohrling, PhD, senior director, Mission and Scientific Affairs at the Huntington’s Disease Society of America, voiced his support for immunotherapy as a potential therapy. “It makes sense to me that our community of scientists and researchers should at least pursue that and determine whether early response to those [inflammatory] markers could have a beneficial effect on patients with HD,” he said.
One of the biggest breakthroughs in recent years comes in the form of antisense oligonucleotides (ASOs); these are DNA molecules that bind to Huntington’s disease-causing RNA and degrade them. Because the molecules are fairly large, they can’t be taken orally; instead, patients receive them via lumbar puncture. The molecules are able to penetrate the surface of the brain, with the hope that they can disseminate more deeply and perhaps reach the basal ganglia—the area of the brain most affected by Huntington’s disease.
The results of a phase 1 trial involving 46 adults with early-stage Huntington’s disease showed that monthly ASO therapy, with increasing doses over 4 months, yielded positive results. The results were presented at a scientific conference a few months ago to a welcoming crowd. “The trial showed in a dose-dependent manner that it lowered Huntington’s protein levels in cerebrospinal fluid,” Dr Yohrling said. “The excitement in the room was fantastic. There were scientists in the room who were crying.”
Researchers who study Huntington’s disease had earlier been cheered by the results of a trial of the drug nusinersen that treats spinal muscular atrophy (SMA), a rare genetic disease. SMA affects children, progressively weakening their muscles and often impairing their breathing. A clinical trial was halted when it became obvious that the participants receiving nusinersen via ASO therapy were able to move better and live longer than the control groups, and researchers realized it was important for all subjects to receive the drug.
Nusinersen recently won an approval from the US Food and Drug Administration, and those in the Huntington’s disease community have similar high hopes for a drug for their patient community. “They’ve developed an ASO that’s delivered in the same manner, intrathecally, into these very, very sick kids,” said Dr Yohrling, referring to the nusinersen success. “It showed all of us that ASOs could make them better.”
The results from the SMA trials, along with the preliminary results of ASO trials for Huntington’s disease, have finally allowed the medical community to picture a meaningful change for Huntington’s patients and those at risk of the disease. “It’s really created this sense of optimism and hope that we’ve never experienced before,” said Dr Yohrling.
One more potential method of ASO treatment is the introduction of gene-silencing material into the brain using harmless viruses as vectors, which requires a neurosurgical procedure. Although it’s more invasive than a lumbar puncture, this treatment does have the potential to get more deeply into the brain. It also involves a single treatment versus monthly infusions. But not all experts are sold on the idea of a one-time treatment.
“You could argue that’s a plus,” said Dr Yohrling. “[But] once the virus is injected, that gene is turned on forever and there’s no off switch. We’ve never done this before in Huntington’s disease patients.”
With all of these new developments, is a cure for Huntington’s disease on the horizon?
“I don’t personally like the cure word,” said Dr Yohrling. “We’re on the precipice of finding effective therapies. We’ll get to the point where Huntington’s disease is a manageable disease, much like HIV is now. I’m hopeful that the drugs we’re developing now will lower the Huntington’s disease burden in the brains of patients.”
Dr Ross agreed. “Now, all of a sudden because of the new genetic techniques, there is a lot of hope to be able to change the course of the disease, maybe even stop it,” he said. “Maybe even reverse it. There’s lots on the horizon.”
Ms. Saloman is a health writer with more than 20 years of experience working for both consumer-and physician-focused publications. She is a graduate of Brandeis University and the Medill School of Journalism at Northwestern University. She lives in New Jersey with her family.