top of page

Antisense oligonucleotide gene therapy for treating Huntington's disease

A potential gene therapy

Huntington’s disease (HD) is an inherited neurodegenerative disease caused by a CAG extension in exon 1 of the huntingtin gene. An extended polyglutamine tract in the huntingtin protein is developed due to the expanded alleles, resulting in intracellular signalling defects.  


Antisense Oligonucleotide (ASO) gene therapy is currently being pioneered to treat HD. In this therapy, oligonucleotides are inserted into cells and bind to the target huntingtin mRNA. Thus, inhibiting the formation of the huntingtin protein by either physically blocking the translation of mRNA (figure 1) or by utilising RNase H to degrade the mRNA. Previous ASO gene therapy experiments conducted on R6/2 mice that express the human huntingtin gene have been successful. In HD research, the R6/2 mouse model is commonly used to replicate HD symptoms and is therefore useful for testing potential treatments. The transgenic R6/2 mouse has an N-terminally mutant Huntingtin gene with a CAG repeat expansion within exon 1.  

In this successful experiment, scientists treated one group of R6/2 mice with the ASO treatment that suppresses the production of human huntingtin mRNA, and saline solution was administered to the control group of mice. This experiment aimed to confirm if ASO therapy improves the survival rate in the R6/2 mice. The results showed that human huntingtin mRNA levels of the mice treated with ASO therapy were lower than the control group. Furthermore, the mice treated with ASO therapy had a higher percentage of survival and lived longer (21 weeks), in comparison to the control group mice that survived until 19 weeks. Thus, it could be concluded that if less human huntingtin mRNA was present in the ASO group, then less human huntingtin mRNA would be translated, and so there would be less synthesis of the huntingtin protein, in contrast to the control group. 


The results of this study are enormously informative in understanding how gene therapy can be used in the future to treat other neurological diseases. However, before ASO therapy is approved for clinical use, further trials will need to be conducted in humans to verify the same successful outcomes as the R6/2 mice. If approved, then the symptoms of HD, including dystonia could be safely controlled with ASO therapy. Furthermore, scientists need to consider that an increased survival rate of only an additional two weeks, as shown in the experiment does not always correlate to an increased quality of life for the patient. Therefore, it needs to be established if the benefits of ASO gene therapy will outweigh the risks associated with it. 


Furthermore, the drug PBT2, which influences copper interactions between abnormal proteins, is currently being studied as a potential treatment option for HD. Some studies have inferred that the aggregation of mutant huntingtin proteins could be due to interactions with metals, including copper. Therefore, this drug is designed to chelate metals and consequently, decrease abnormal protein aggregations in the body. This treatment has been shown to improve motor tasks and increase the lifespan in R6/2 mice. However, as this treatment has a lot of shortcomings, further studies need to be conducted over a large period of time to confirm a successful outcome of this drug on HD patients. 

Written by Maria Z Kahloon





Kordasiewicz HB, Stanek LM, Wancewicz EV, Mazur C, McAlonis MM, Pytel KA, et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron. 2012;74(6):1031–44. 

Valcárcel-Ocete L, Alkorta-Aranburu G, Iriondo M, Fullaondo A, García-Barcina M, Fernández-García JM, et al. Exploring genetic factors involved in Huntington disease age of onset: E2F2 as a new potential modifier gene. PLoS One. 2015;10(7):e0131573. 

Liou S. Antisense gene therapy [Internet]. 2010 [cited 2021 Aug 6]. Available from:   

Huntington's disease research study in R6/2 MOUSE model: Charles River [Internet]. Charles River Labs. [cited 2021 Aug 26]. Available from: 

Frank S. Treatment of Huntington's disease. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. Springer US; 2014;11(1):153-160.  

Potkin KT, Potkin SG. New directions in therapeutics for HUNTINGTON DISEASE. Future neurology. 2018;13(2):101-121. 

Project Gallery

bottom of page