Less than a month after researchers unveiled that a “ticking DNA clock” is behind Huntington’s disease (HD), scientists have now identified an antisense oligonucleotide (ASO) that can slow down the disease-causing gene expansion process.
In human neurons grown in the lab, treatment with the ASO stopped expansion of the gene compared to control. Further, the compound reduced levels of the targeted protein in the central nervous systems of mice.
The results of the study, led by neurologist Sarah Tabrizi, Ph.D., were published in Science Translational Medicine on Feb. 12. Tabrizi is the director of the Huntington’s Disease Centre at University College London.
The researchers studied different doses in order to help future clinical trial design, they wrote in their paper.
The effect of the ASO was dose-dependent, and the team found that lowering the targeted protein by 83% completely stopped gene expansion, according to a Feb. 12 press release.
Huntington’s is a progressive neurodegenerative disease caused by an inherited mutated copy of the huntingtin gene. Symptoms like uncontrolled movements and trouble with mobility and cognition typically appear in midlife, and the disease is ultimately fatal.
The ASO is designed to bind to mRNA that codes for a protein called MSH3, a pivotal tool in the cell’s DNA repair arsenal, and flag it for destruction. A past study by Tabrizi and colleagues found that certain variations of the MSH3 gene led to patients with Huntington’s having slower disease progression, implicating the molecule as a potential target for new therapies.
In a paper published last month, researchers led by Steven McCarroll, Ph.D., of the Broad Institute of MIT and Harvard, found that Huntington’s is caused not by a toxic buildup of the huntingtin protein but by the expansion of repeated segments of DNA called CAGs in the gene itself. As the gene gets longer over time, it eventually hits a toxic threshold that causes the neuron to die.
McCarroll is also an author of the new study.
“Our study finds that ASO-mediated MSH3 knockdown prevents CAG repeat expansion” without disrupting normal cell functioning, the authors wrote, “underscoring its potential for the treatment of HD and other repeat expansion disorders in which MSH3 is implicated.”
Some of those other repeat expansion disorders include myotonic dystrophy, fragile X syndrome and some forms of amyotrophic lateral sclerosis.