Targeted Drug May Slow Huntington’s Disease Progression

cell mRNA
cell mRNA
A new drug that inhibits the production of HTT mRNA may help slow progression of Huntington's disease.

The first potential drug to target the inhibition of huntingtin protein in people with Huntington’s disease proved to be safe and effective in an animal study, researchers reported.

The full study results will be presented at the 2016 American Academy of Neurology Annual Meeting in Vancouver, April 15-21, 2016.

The drug, IONIS-HTTRx, which was granted Orphan drug designation by the FDA earlier this year, may be the first to succeed in silencing the HTT gene malfunction, ultimately altering the clinical course of the neurodegenerative disease.

Previous pharmacological rodent studies have shown that delivery of antisense oligonucleotides (ASO) that target HTT mRNA slow disease progression and result in sustained reversal of disease phenotype.

In the current study, ASOs were designed and tested in 2 transgenic mouse models of Huntington’s disease. In YAC128 mice, motor deficits improved within 1 month of antisense treatment and were restored to normal at 2 months after termination of treatment. In BACHD mice, motor skills improved 8 weeks after antisense treatment initiation and persisted for at least 9 months after treatment was terminated.

IONIS-HTTRx, a second generation 2′-O-methoxyethyl chimeric ASO with mixed backbone and high specificity for human HTT mRNA was further studied in monkeys at doses up to 20 mg. Dose-dependent reductions in HTT mRNA and huntingtin protein throughout the central nervous system were observed, with no dose-limiting side effects. Reduction of cortical huntingtin levels reached 50% in monkeys and correlated with a 15 to 20% reduction in the caudate.

The results of the animal studies have informed an ongoing Phase 1/2a human clinical trial, ISIS-443139-CSI, a multi-center, randomized, double-blind, placebo-controlled study with the purpose of assessing increasing doses of intrathecally administered IONIS-HTTRx in patients with early-onset Hungtington’s disease. In the trial, the drug is administered in 4 doses at monthly intervals, with different doses being evaluated for safety and tolerability. The researchers also hope to characterize the drug’s pharmacokinetics and measure its effectiveness against several endpoints, including neuroimaging, electrophysiological, clinical, and biochemical outcomes.

Although the drug is still years of way from use in clinical practice, the results are promising.

“It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease,” principal investigator Blair R. Leavitt, MD, of the University of British Columbia in Vancouver, said in a statement. “Right now we only have treatments that work on the symptoms of the disease.”


Leavitt BR, Tabrizi S, Kordasiewicz H, et al. Discovery and Early Clinical Development of ISIS-HTTRx, the First HTT-Lowering Drug to be Tested in Patients with Huntington’s Disease. Presented at: American Academy of Neurology Annual Meeting 2016; April 15-21, 2016; Vancouver.