Antisense Oligonucleotides

Huntington’s disease is a heritable neurodegenerative disorder characterized by uncontrolled tremors (chorea), cognitive impairment, and psychiatric problems.

Antisense oligonucleotides are a type of gene silencing treatment for Huntington’s disease. Several of them are currently in development by pharmaceutical companies.

How do antisense oligonucleotides work?

Huntington’s disease is caused by mutations in the huntingtin (HTT) gene, which introduce long segments of repeating CAG nucleotides in the gene.

When a protein is being made, a gene is first “transcribed” or copied into a molecule called a messenger RNA. This messenger RNA then serves as a template for cells to make the corresponding protein.

The mutation seen in Huntington’s disease results in an abnormally large HTT protein being made, which is then degraded by the cell. This leads to the formation of toxic protein fragments, which damage the cells and cause neurodegeneration. Huntington’s disease is a dominant trait, meaning that a single copy of the mutated gene will cause the disease, even if the other gene copy is normal.

Antisense oligonucleotides are artificially created nucleotides, or pieces of DNA, which are complementary to the mutated sequence of the HTT messenger RNA. The antisense oligonucleotide binds to the HTT messenger RNA and prevents it from being translated into protein. In this way, the gene is “silenced,” or blocked, from creating toxic proteins.

Preclinical studies have shown promising results, and clinical trials are ongoing for several antisense oligonucleotides.

Antisense oligonucleotides in clinical trials

IONIS-HTTRx is an antisense oligonucleotide treatment for Huntington’s disease initially developed by Ionis Pharmaceuticals and now licensed to Roche.

Recent Phase 1/2 clinical trial results (NCT02519036) showed that IONIS-HTTRx was able to decrease levels of abnormal HTT protein being produced in early-stage patients.

An open-label extension trial (NCT03342053) to assess the long-term safety and effectiveness of this compound is still ongoing.

Wave Life Sciences is developing two antisense oligonucleotides, WVE-120101 and WVE-120102, both of which are in Phase 1b/2a clinical trials and recruiting Huntington’s disease patients in Toronto and Poland.

The first trial, called PRECISION-HD1 (NCT03225833), is recruiting adults with early manifest Huntington’s disease who carry a targeted single nucleotide polymorphism (SNP) called rs362307, one of the most common mutations causing Huntington’s disease. During the trial, patients will receive single or multiple doses of WVE-120101 or a placebo. Symptoms, as well as HTT protein levels, will be monitored.

The second trial, PRECISION-HD2 (NCT03225846), is recruiting adults with early manifest Huntington’s disease who carry a different targeted SNP called rs362331. Patients will receive single or multiple doses of WVE-120102 or placebo. Symptoms and HTT protein levels will be monitored throughout the study.

Other information

Antisense oligonucleotides are a relatively new type of treatment; it is not yet clear what side effects they may cause.


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