Images from cases courtesy of A.Prof Frank Gaillard, Dr Mostafa Mahmoud El Feky |

Rewriting Life

Gene-altering treatments are medicine’s best shot yet against Huntington’s disease

After 25 years, scientists are starting to make progress against the devastating illness.

For 15 years, Michelle Dardengo watched helplessly as her father lost his memory and became more and more depressed. As his body failed, too, he could no longer take care of himself. He died in 2003 at age 68. Huntington’s disease had robbed him of a longer life.

But for Dardengo, who lives in Vancouver, Canada, the pain was not only in losing him. She knew there was a 50-50 chance that she had inherited the genetic mutation responsible for his death.

She began noticing the warning signs in herself in 2015, when she was 52. At her work, which involved debugging software, she had trouble keeping up. Walking her dogs every day, she saw her balance start to falter. When she went to a doctor about the symptoms, she already knew the grim diagnosis.

As she faces it, however, Dardengo has a sliver of hope. She has joined a study testing an experimental drug meant to stave off the ravages of the disease.

Huntington’s is a genetic disorder that causes nerve cells in the brain to gradually break down, leading to irreversible brain damage. There is no cure—only drugs to help manage the side effects, like depression and involuntary movements. Eventually, people lose their ability to think, walk, and speak.

The drug Dardengo is trying, made by Ionis Pharmaceuticals, is one of a handful of new therapies in development that aim to alter the genetic root of the disease and thus slow or reverse the damage. Scientists have known the cause of Huntington’s for 25 years—an error in a particular gene. But because drugs take so long to develop, only now are genetic treatments beginning to trickle out of the lab to treat the first patients.

A long road

Michelle Dardengo in 2016.

Researchers discovered the Huntington’s gene, HTT, in 1993 by studying families affected by the disease. All human beings carry this gene, but people with Huntington’s have a mutated version that contains repeated segments—extra letters of DNA that shouldn’t be there, like a genetic stutter.

Eventually, scientists realized that these repeats cause the gene to make abnormal versions of a protein called huntingtin. In its normal form, this protein is needed for brain development, but aberrant ones clump together in the brain’s nerve cells like balls of spaghetti and cause damage over time.

It proved difficult to treat the disease with conventional “small molecule” drugs, which can be easily made into tablets or capsules. Now scientists are working on treatments that, rather than target the huntingtin protein, try to prevent it from being produced in the first place. These new therapies are meant to stop the disease in its tracks, instead of just treating symptoms as traditional drugs do.

Ionis’s experimental drug uses a technique known as “gene silencing,” or antisense, which involves using strands of chemically modified DNA to essentially gum up the genetic copying mechanism before it can produce harmful huntingtin proteins from the HTT gene.

In a small clinical trial, whose initial results were reported in December, the drug reduced levels of huntingtin in 46 people with early Huntington’s disease—making it the first ever to do so. “The responses we are seeing are as good as we could possibly hope for,” says Blair Leavitt of the University of British Columbia, who headed the trial in Canada. Swiss drug giant Roche has partnered with Ionis to continue development of the drug.

Dardengo was the first patient in that trial to receive the injections, which take about 40 minutes and involve inserting a large needle into the spine so the cerebrospinal fluid can carry the drug to the brain. She still doesn’t know whether she got the drug or a placebo, and in fact, her symptoms haven’t improved yet. But, she says, “the chance of being a placebo didn’t matter to me. Sometimes I feel like I won the lottery.”

The next phase of the trial will last longer and enroll several hundred patients across North America. Dardengo will be one of them.

Frank Bennett, head of research at Ionis, says if the drug works, the goal will be to treat patients as early as possible, maybe even before they start showing any symptoms. “Our hope is that we could stabilize people, and there’s a possibility that some of their symptoms can actually be reversed and they could get better,” he says.

For families like Dardengo’s, that could be life-changing. In the US, about 30,000 people have Huntington’s disease and more than 200,000 people have inherited the genetic mutation from a parent. A person needs only one copy of the faulty gene to develop the disorder. That means a child of a parent with Huntington’s has a 50 percent chance of getting it. 

Like many parents with Huntington’s, Dardengo has always feared that her children (she has two, both in their 20s) and her future grandchildren will end up with the disease. In addition to her father, her grandfather had Huntington’s, and so did four of his siblings. Now, though, she doesn’t worry as much about the future. She’s optimistic that the Ionis drug will work.

“The biggest difference that a success in the trial would make is a sense of hope for families,” says Leavitt. “There’s never been anything that’s had any effect on this disease.” 

Other approaches

Several other gene-based attacks on Huntington’s are in the works. Wave Life Sciences is testing two gene-silencing therapies in clinical trials. Sangamo Therapeutics, Spark Therapeutics, and UniQure are developing gene therapies that use an engineered virus to transport genetic material to brain cells to stop production of the abnormal huntingtin. 

Brain surgery would be required to deliver these therapies, but researchers think it would be a one-time procedure, as is the case for other gene therapies. Steven Zelenkofske, chief medical officer at UniQure, says the company is planning to begin a clinical trial by the end of this year or the beginning of 2019.

Some researchers are investigating even newer techniques, like inserting the gene-editing tool CRISPR into human cells, which can then use it as a weapon against the mutated gene.

Even if these approaches work, it could take a year or more for patients to start seeing the effects. And since Huntington’s gets worse over time, it will take even longer to know whether those effects are lasting.

Still, families and researchers are enthusiastic about the new wave of treatments, says George Yohrling, senior director of scientific affairs at the Huntington’s Disease Society of America. The organization’s call center and website for connecting Huntington’s patients to clinical trials saw a four-fold increase in calls and traffic in December after Ionis announced its initial results. “There’s an excitement in the community that I’ve never experienced before,” Yohrling says.

That excitement could still run into some harsh realities. Brain diseases are notoriously difficult to treat. Over the past two decades, drug makers have launched 99 clinical trials investigating 41 different compounds for Huntington’s, but only two drugs have been approved—and those are just to manage symptoms.

Dardengo knows she may not benefit from the drug, but that hasn’t dimmed her optimism. “Even if this doesn’t help me, it’s a chance to help other people with this disease,” she says.