skip to main content

Silencing a killer: Mutant HTT gene selincing as a therapy for Huntington Disease

April 5, 2016

Feb. 16, 2016 –  

  • Date and time: February 16, 2016 from 2:00-3:00 PM
  • Location: 310 Kelly Hall 
  • Speaker: Amber L. Southwell, Ph.D.
  • Affiliation: Centre for Molecular Medicine and Therapeutics, University of British Columbia

Huntington disease (HD) is caused by a polyglutamine expansion encoded by a CAG tract in exon 1 of the huntingtin (HTT) gene to greater than 36 repeats. Silencing of the mutated HTT gene promises to correct behavioral, biochemical, molecular, and neuropathological changes with HD. However, preclinical attempts thus far been non- selective reducing both mutant and wild-type HTT. Since HTT protein is important for neuronal health throughout life, we focused our studies on attempts to selectively correct the mutated HTT allele. Using population genetics, we identified therapeutically relevant disease causing single nucleotide repeats (SNPS) and generated a humanized mouse model of HD, Hu97/18. We then developed antisense oligonucleotides (ASOs) that target the affected HD-SNPs to accomplish allele-specific suppression of mutant HTT. We identified potent and well-tolerated ASOs that selectively silence mutant HTT at a broad range of doses throughout the central nervous system for 36 weeks or more after a single treatment. We further show that in Hu97/18 mice, this allele-specific mutant HTT suppression prevents HD-like behavioral and neuropathological changes. In addition, to facilitate translation of this therapy to the clinic, we have developed an ultrasensitive method for mutant HTT detection from cerebrospinal fluid suitable for use in HD mice and patients and demonstrated that CSF mutant HTT reflects brain mutant HTT, increasing with diseases stage and decreasing following brain HTT suppression. This assay can be fairly rapidly translated for human applications.

For more information, contact Anne Wailes at

* Amber Southwell Talk flyer.pdf
Download pdf Format