RNAi Therapies

Gene silencing by RNA interference (RNAi) is a therapeutic approach for the treatment of Huntington’s disease that is currently in development. The goal of this strategy is to reduce the amount of abnormal huntingtin (HTT) protein being produced in cells.

How RNAi therapy for Huntington’s disease works

Huntington’s disease is caused by a mutation in the (HTT) gene, which results in the production of an abnormally large protein. The defective HTT protein accumulates in nerve cells and causes their death. This leads to the decline in motor and cognitive abilities seen in Huntington’s disease patients.

RNAi is a type of gene-silencing therapy, the goal of which is to decrease the production of faulty HTT protein. A gene serves as a template for a protein to be made. The protein is not made directly from the gene, but from an intermediate molecule called messenger RNA, or mRNA. mRNA is kind of a blueprint of the gene that can travel from the cell nucleus, where the genes are stored, to the cytoplasm, where the proteins are made.

mRNA is a short-lived molecule needed for protein production. The amount of protein made can be regulated at the mRNA level; once an mRNA is degraded, it can no longer serve as a template to make a protein. One mechanism by which the degradation may occur is through RNAi and involves so-called microRNAs (miRNAs). These are short RNA molecules that bind to part of the mRNA and trigger either the degradation process or sterically hinder protein production.

In Huntington’s disease, this regulation is out of balance. The production of miRNAs is altered in the brain of Huntington’s disease patients, and the internal degradation mechanism is not sufficient to maintain a healthy level of protein.

RNAi therapy is an approach to deliver miRNAs that degrade HTT mRNA so that the amount of HTT protein decreases.

The current approach for RNAi therapy is to deliver the miRNA with the help of adeno-associated viral (AAV) vectors. These are modified viruses in which the disease-causing genes have been removed and replaced by miRNA that binds to HTT mRNA.

Investigational RNAi therapies

Two investigational RNAi therapies for Huntington’s disease, AMT-130 and VY-HTT01, are currently in development.


AMT-130 is an RNAi therapy candidate by uniQure. Both the U.S. Food and Drug Administration and the European Medicines Agency recently granted AMT-130 orphan drug status. UniQure plans to submit an investigational new drug application to the FDA for the treatment later in 2018, which is a necessary first step toward clinical trials.

A proof-of-concept study in a mouse model of Huntington’s disease showed that a one-time administration of AAV-delivered miRNA is sufficient to silence the HTT gene and reduce HTT protein levels.

A preclinical study in non-human primates showed that AMT-130 is widely distributed in the brain and spinal cord after injection.

In another study with minipigs, AMT-130 was widely distributed throughout the brain three months after administration, and the level of HTT protein was more than 50% reduced in regions that were reached by AMT-130.


VY-HTT01 is being developed by Voyager Therapeutics in collaboration with Sanofi-Genzyme and the CHDI Foundation. Voyager plans to submit an investigational new drug application to the FDA for VY-HTT01 in 2018.

A preclinical mouse study showed that the AAV vector reached the majority of brain cells and that HTT levels were significantly reduced.

Results of another study in non-human primates showed that AAV vectors could be delivered to relevant regions of the brain, a prerequisite for a successful gene-silencing therapy.


Huntington’s Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.