A novel antisense oligonucleotide (ASO) drug can reduce the levels of mutant huntingtin protein (HTT) in the cerebrospinal fluid (CSF) of patients with Huntington disease (HD), according to a new study published in the New England Journal of Medicine. This finding positions the drug, known as HTTRx, as a promising therapeutic for HD and opens up the possibility of using ASO drugs to treat other neurodegenerative diseases.

Credit: Philip Patenall/Springer Nature Limited

HD is caused by a CAG repeat expansion in the HTT gene (HTT), and the resulting mutant protein product causes dysfunction and death of neurons. Current therapies for HD only treat the symptoms, which include movement, cognitive and psychiatric impairments, but evidence from animal models suggests that reducing the levels of mutant HTT can alter the disease course.

HTTRx is a synthetic oligomer that binds to HTT mRNA and causes it to be degraded, thereby inhibiting translation of the HTT protein. Previous studies in animal models showed that HTTRx could lower HTT protein levels and improve disease-associated phenotypes, but the new study was the first time the drug had been given to humans.

The study, led by Sarah Tabrizi, included 46 patients with HD who were treated with placebo or one of five doses of HTTRx, in an ascending-dose design. Patients received four bolus intrathecal injections at 4-week intervals and were monitored for four further months. “This duration was expected to be sufficient to evaluate safety and tolerability of the ASO, which was the primary objective of the study,” explains Tabrizi. In addition, the study team took CSF samples from patients before each administration of drug or placebo, and at either 28 or 56 days after receiving the last dose. These samples enabled the team to characterize the pharmacokinetics of HTTRx and to explore the effects of treatment on levels of mutant HTT.

HTTRx administration induced a dose-dependent reduction in the concentration of mutant HTT in CSF at the 28-day post-treatment time point. With the highest two doses, levels were reduced by 40–60% from baseline measurements. However, the team did not observe a difference in functional, cognitive, psychiatric or neurological measures in patients treated with HTTRx compared with those who received placebo.

“Now that we can significantly reduce mutant HTT in the CNS, the next step is to demonstrate that doing so provides meaningful benefit to patients,” explains Tabrizi. “For this, we need larger, longer clinical trials.” These further trials are already underway, and Tabrizi points out that the results of this initial study also have broader implications.

This study is the first to demonstrate antisense-mediated protein suppression in patients with a neurodegenerative disease

“This study is the first to demonstrate antisense-mediated protein suppression in patients with a neurodegenerative disease,” she says. “These data suggest that antisense technology has the potential to provide disease-modifying benefits in other neurodegenerative diseases associated with aberrant production of proteins, including amyotrophic lateral sclerosis and Alzheimer disease.”