Skip to main content
Publications of the Week

A Comprehensive Haplotype Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease

By November 25, 2019No Comments

Read the Publication

This week we profile a recent publication in the American Journal of Human Genetics from Dr. Chris Kay
(pictured) in the laboratory of Dr. Michael Hayden at the Center for Molecular Medicine and Therapeutics.

Can you provide a brief overview of your lab’s current research focus?

Our lab works on advancing therapeutic strategies for the treatment of Huntington disease (HD), with a focus on molecular mechanisms and gene silencing approaches.

What is the significance of the findings in this publication?

In HD, the mutated HTT gene expresses with pathogenic gain-of-function activities. Gene silencing of HTT has emerged as a major therapeutic strategy for HD, with gene silencing compounds now in human clinical trials. However, HTT has important endogenous functions and only one copy of HTT is mutated in patients. Approaches to selectively silence mutant HTT while preserving expression of the normal HTT copy may therefore be important for long-term safety and efficacy of HTT silencing therapies.

In our study, we present a comprehensive analysis of the HTT gene in nearly 2000 HD patients from 13 distinct populations across five continents, revealing which alleles of HTT offer targets for therapeutic suppression of mutant HTT in the most patients. Our study provides a critically important road map to the development of selective HTT silencing therapies for HD patients from a range of ethnically distinct populations around the world.

What are the next steps for this research?

We are currently developing gene-silencing drug candidates, called antisense oligonucleotides (ASOs), to target novel alleles revealed by our study. These candidate drugs could be developed to treat HD patients in numerous populations highlighted in our study, such as Southern Europeans, South Asians, and individuals of Middle Eastern ancestry, who may be poorly served by selective HTT silencing drugs now in clinical trials.

This work was funded by:

Yes, our work was supported by the Canadian Institutes of Health Research as well as the ERA-Net E-Rare Consortium.

Read the Publication