As the sun went down on a recent Friday, the hospital clinic buzzed with activity. “Loads of patients turned up without appointments,” says Sarah Tabrizi, a neurologist at University College London.
It wasn’t just the typical post-holiday rush. Many rushed in, Tabrizi suspects, after hearing news last month about a potential new therapy for Huntington’s disease, a brain disorder that cripples the body and blurs speech and thinking, sometimes not too long after a person’s 30th birthday. Like other neurodegenerative disorders such as Lou Gehrig’s, Parkinson’s and Alzheimer’s, Huntington’s has no cure. Over decades biotech companies have poured billions of dollars into developing and testing pharmaceuticals for these devastating conditions, only to unleash storms of disappointment. Yet in December a ray of something approximating hope poked through when a California company released preliminary findings from its small Huntington’s study.
Results from this early-stage clinical trial have not yet been published or reported at medical meetings. But some researchers have growing confidence that the drug should work for Huntington’s and perhaps other diseases with clear genetic roots. The initial data showed enough promise to convince Roche to license the drug from California-based Ionis Pharmaceuticals, which sponsored the recent Huntington’s trial. The pharma giant paid Ionis $45 million for the right to conduct further studies and work with regulatory agencies to bring the experimental therapy to market.
Huntington’s is heritable—a copy of the gene from either parent guarantees a person will develop the disease. Each case can be traced to a bunch of repeated code letters of DNA within a single gene called HTT. Brain cells translate that genomic gobbledygook into rogue proteins, which do bad things inside nerve cells and eventually trigger symptoms, such as involuntary movements. Most experimental drugs target the cells’ misdeeds. But designing drugs gets tricky if researchers are not sure which, if any, of those problems actually drives disease, and which act earlier or later in the process.
With Ionis’s approach, none of that matters. The drug in question tries to keep cells from making the mutant protein in the first place. DNA in the cell nucleus normally consists of a twisted double strand of molecules called nucleotides. Ionis’s drug, called an antisense oligonucleotide, is a snippet of single-stranded DNA. It halts an intermediate step in the protein-making process by binding to genetic material known as RNA, blocking the issuing of final instructions for making the Htt protein.
The strategy of using designer DNA drugs to shut down production of disease-causing genes in neurodegenerative disorders has been in the making for more than a decade. It was pioneered by Don Cleveland, a neuroscientist at the University of California, San Diego, and Richard Smith director of the Center for Neurologic Study. A consultant for Ionis, Cleveland won a 2018 $3-million Breakthrough Prize in Life Sciences for his antisense work, which showed reducing mutant protein levels can slow disease in laboratory animals used to study Huntington’s and Lou Gehrig’s diseases.
The recent human trial, led by Tabrizi, enrolled 46 people with early Huntington’s disease at nine sites in the U.K., Germany and Canada. The researchers injected either the antisense drug or a placebo into the study participants’ spinal fluid—a 20-minute procedure similar to those that deliver epidural anesthesia to women in labor. In the Huntington’s trial participants received three months of injections delivered at four-week intervals and returned to the lab for tests three to four months after the final dose.
Despite promising results from past studies in rodents and nonhuman primates, testing the antisense strategy in people carried big unknowns. “We didn’t know if [the drug] would get into the brain,” Tabrizi says. “We didn’t know if we’d be able to switch off the HTT message. We didn’t know if it would be safe.”
After collecting the participants’ spinal fluid and tallying final measurements of mutant Htt, the results were clear: Antisense therapy was not only safe and well tolerated, it reduced the targeted disease-causing protein.
Neuroscientist John Hardy, a University College London colleague not involved in the study, found the results a complete surprise. “It’s all very well to give antisense therapies to a mouse with a 300-milligram brain,” he says. “But to give spinal fluid injections [in people] and have it spread through the brain to an extent great enough to knock down gene expression….” He adds: “Three or four years ago, I would not have expected that to work, and yet it does. This could be a whole new generally applicable type of drug.”
Part of Hardy’s excitement stems from the recent success of antisense drugs in spinal muscular atrophy (SMA), an inherited neuromuscular disorder in children. Two SMA trials were stopped in 2016 after analyses showed kids taking the drug exhibited motor improvements so dramatic, regulators deemed it unethical to keep some participants on the placebo. The U.S. Food and Drug Administration approved the SMA drug, nusinersen, later that year.
Because antisense drugs are built from the same set of core elements—chemical modifications that stabilize a chain of nucleotides and help deliver them inside cells—they can be developed more quickly than traditional protein-targeting therapies. “Once we establish the basic principles, we can apply those for the next drug and the next,” says Frank Bennett, Ionis’s senior vice president of research. “It really streamlines the development process.” In addition to Huntington’s, Ionis has begun testing antisense therapies for certain types of Lou Gehrig’s and Alzheimer’s—and more trials are in the planning stages.
The recent Huntington’s success “is the first step in a journey,” Tabrizi says. Next up: a larger trial in hundreds of patients to see if lowering mutant Htt protein slows progression of the disease, then a trial in healthy people who carry the mutant HTT gene to see if antisense treatments could prevent Huntington’s altogether.