In Vivo Evaluation of Candidate Allele-specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides
| Autor: | Holly Kordasiewicz, Michael R. Hayden, Clarence Frank Bennett, Crystal N. Doty, Erika B. Villanueva, Punit P. Seth, Kuljeet Vaid, Susan M. Freier, Niels H. Skotte, Eugenia Petoukhov, Amber L. Southwell, Jeffrey B. Carroll, Michael E. Østergaard, Eric E. Swayze, Andrew T. Watt, Yuanyun Xie |
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| Rok vydání: | 2014 |
| Předmět: |
Huntingtin
Mutant Nerve Tissue Proteins Single-nucleotide polymorphism Biology Polymorphism Single Nucleotide Injections Rats Sprague-Dawley Mice Drug Discovery Genetics Huntingtin Protein Animals Humans Gene silencing Gene Silencing Molecular Targeted Therapy Cognitive decline Molecular Biology Pharmacology Oligonucleotide Brain Oligonucleotides Antisense Thionucleotides Molecular biology Rats 3. Good health Mice Inbred C57BL Disease Models Animal Huntington Disease Humanized mouse Cancer research Molecular Medicine Mutant Proteins Original Article |
| Zdroj: | Molecular Therapy. 22:2093-2106 |
| ISSN: | 1525-0016 |
| DOI: | 10.1038/mt.2014.153 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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