Conference Coverage

New Drug Technology Could Treat Huntington’s Disease

A first-in-man trial examined an antisense oligonucleotide intended to suppress huntingtin RNA.


SAN DIEGO—Developments in strategies based on CRISPR and antisense oligonucleotides (ASOs) have raised the prospect that these therapies targeting genetically caused diseases could one day benefit patients with Huntington’s disease, according to an overview provided at the 142nd Annual Meeting of the American Neurological Association. Researchers aspire to conduct clinical trials in people who carry the risk gene for Huntington’s disease, but for whom disease onset is 20 or 30 years away. “If we can dose them early enough, we might be able to … delay or prevent onset,” said Sarah Tabrizi, MBChB, PhD, Joint Head of the Department of Neurodegenerative Disease at University College London.

Sarah Tabrizi, MBChB, PhD

A Rare, Progressive Dementia

Huntington’s disease is the most common genetic dementia. Its prevalence is approximately one in 8,000. The disease is caused by a mutation in the first exon of HTT that influences the number of CAG trinucleotide repeats. A person with more than 40 CAG repeats will develop the disease. This number of repeats results in the production of an elongated version of the huntingtin protein, which subsequently is cleaved into toxic segments that accumulate in neurons. Disease onset typically occurs between the mid-30s and 40s.

Initial symptoms of Huntington’s disease include irritability, poor coordination, indecision, and chorea. Symptoms worsen as the disease progresses, and patients may develop personality changes and difficulty walking, swallowing, and thinking. Survival ranges from 15 to 20 years from symptom onset.

New Drug Modalities Have Many Potential Targets

Many pathogenic mechanisms contribute to the onset of Huntington’s disease and could be therapeutic targets. “Targeting DNA or RNA is absolutely critical,” said Dr. Tabrizi. “It does not matter what the downstream cellular pathway is. If you target proximally, you have more chance of achieving a therapeutic benefit in neurodegeneration.”

Many efforts to develop a therapy for Huntington’s disease focus on huntingtin transcription and translation. The aim is to lower the amount of mutant huntingtin in the brain. For example, studies of zinc finger proteins targeting DNA are in early preclinical development. Other investigators are using RNA interference to target huntingtin messenger RNA (mRNA) or ASOs to target huntingtin mRNA.

Data suggest that the CRISPR technique can remove the excess CAG repeats in cell lines. This technique is based on a naturally occurring genome-editing system that identifies viruses and cleaves their DNA, but it may be decades before this method is able to treat the whole human brain, said Dr. Tabrizi.


She and her colleagues are studying an ASO as a therapy for Huntington’s disease. These molecules are short pieces of chemically modified DNA or RNA that can be diffused rapidly and easily enter cells in the CNS. They are stable, their effects are reversible, and they allow for dose titration. Dr. Tabrizi’s group is analyzing an ASO with 20 base pairs that recognizes and degrades the huntingtin mRNA transcript. The molecule’s chemical modifications give it high affinity, stability, and tolerability, and it is delivered intrathecally.

A preclinical study in nonhuman primates provided valuable pharmacokinetic and pharmacodynamic information that influenced the dosing of Dr. Tabrizi’s current, ongoing trial in humans. The investigators gave monkeys four intrathecal doses of therapy at monthly intervals before sacrificing them. They found that treatment significantly lowered huntingtin RNA levels in the frontal cortex and occipital cortex. The levels were about 50% lower in the caudate and thalamus after treatment, and approximately 75% lower in the hippocampus. Suppression of huntingtin RNA was sustained in the frontal cortex and the caudate for eight weeks, and the reduction was approximately 15% at that time. The ASO reached the deep structures of the brain, but had a predominantly cortical pharmacodynamic effect, said Dr. Tabrizi.

First-in-Man Study Is Complete

Dr. Tabrizi and colleagues have recently completed the first-in-man clinical trial. Their objective was primarily to evaluate the safety and tolerability of multiple intrathecal administrations of the therapy in ascending doses. They intended to obtain more information about the drug’s pharmacokinetics and to look at its effects on mutant huntingtin.

The trial was designed as a phase Ib–IIa study that could lead to a phase III clinical trial if enough data on dosing were obtained. Participants were randomized 3:1 to antisense drug or placebo. Including a placebo group in a first-in-man study was important for investigating drug effects, procedure effects, and the placebo effect, which is large in Huntington’s disease, said Dr. Tabrizi.

Patients received the ASO by a push bolus intrathecal injection through a small-gauge atraumatic needle. Each patient received four doses delivered at 28-day intervals. The follow-up period was 15 weeks.

The first participant received the first dose in September 2015, and enrollment was complete in June 2017. Dr. Tabrizi and colleagues enrolled 46 patients with early-stage Huntington’s disease into the study. Mean age at baseline was 47. Approximately 60% of participants were men. Participants’ mean number of CAG repeats was 44, and the baseline CSF level of mutant huntingtin, mean total functional capacity, and total motor score were consistent with early stage Huntington’s disease.

Intrathecal dosing was well tolerated. “We chose a small-gauge atraumatic needle because … we did not want to have to stop [the trial] because of headaches,” said Dr. Tabrizi. The researchers have not recorded any safety concerns to date, and the results seem to support further development of the therapy, she added.

The follow-up visits are complete, and patients are entering an open-label extension in which all participants will receive active treatment. The extension also will generate long-term safety data. In December 2017, Ionis Pharmaceuticals, which designed the ASO treatment and sponsored the first-in-man clinical study, announced that the study results provide clear evidence of target engagement and reduction in mutant huntingtin protein. Roche, Ionis’s partner in developing the treatment, licensed the drug and will be responsible for all future development. Such activities may include larger, longer studies aimed at determining whether lowering mutant huntingtin protein benefits patients, said Dr. Tabrizi.

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