In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides

Research output: Contribution to journalJournal articlepeer-review

  • Amber L Southwell
  • Skotte, Niels
  • Holly B Kordasiewicz
  • Michael E Østergaard
  • Andrew T Watt
  • Jeffrey B Carroll
  • Crystal N Doty
  • Villanueva, Erika
  • Eugenia Petoukhov
  • Kuljeet Vaid
  • Yuanyun Xie
  • Susan M Freier
  • Eric E Swayze
  • Punit P Seth
  • Clarence Frank Bennett
  • Michael R Hayden

Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than nonselective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. Here we evaluate ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 16 weeks or more after a single intracerebroventricular (ICV) injection. With further validation, these ASOs could provide a therapeutic option for individuals afflicted with HD.

Original languageEnglish
JournalMolecular Therapy
Volume22
Issue number12
Pages (from-to)2093-106
Number of pages14
ISSN1525-0016
DOIs
Publication statusPublished - Dec 2014
Externally publishedYes

    Research areas

  • Animals, Brain, Disease Models, Animal, Gene Silencing, Humans, Huntington Disease, Injections, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Mutant Proteins, Nerve Tissue Proteins, Oligonucleotides, Antisense, Polymorphism, Single Nucleotide, Rats, Rats, Sprague-Dawley, Thionucleotides

ID: 153451191