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In vivo evaluation of candidate allele-specific mutant huntingtin gene silencing antisense oligonucleotides
Amber L Southwell1, Niels H Skotte1, Holly B Kordasiewicz2
1Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Insights
Researchers developed new antisense oligonucleotides (ASOs) to lower toxic mutant huntingtin protein (muHTT) in Huntington disease (HD). These ASOs target specific gene variations, offering a potentially safer and effective therapeutic strategy for HD patients.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene.
- Current treatments for HD are not disease-modifying, highlighting the need for novel therapeutic approaches.
- Mutant huntingtin protein (muHTT) toxicity drives HD pathogenesis, making muHTT lowering a promising therapeutic strategy.
Purpose of the Study:
- To evaluate allele-specific antisense oligonucleotides (ASOs) for lowering mutant huntingtin protein (muHTT) in Huntington disease (HD).
- To assess the safety, efficacy, and pharmacokinetic profile of ASOs targeting HD-associated single nucleotide polymorphisms (SNPs).
Main Methods:
- Utilized a humanized mouse model (Hu97/18) heterozygous for targeted SNPs.
- Conducted in vivo studies including ASO screening, distribution, duration of action, and dosing assessments.
- Administered ASOs via single intracerebroventricular (ICV) injection.
Main Results:
- Identified four lead ASOs that are well-tolerated and effectively lower muHTT.
- Demonstrated potent and selective muHTT silencing across a broad dose range.
- Observed sustained therapeutic effects in the central nervous system for over 16 weeks post-injection.
Conclusions:
- Developed promising ASO candidates for allele-specific muHTT lowering in HD.
- These ASOs show potential as a safe and effective disease-modifying therapy for Huntington disease.
- Further validation could lead to a novel therapeutic option for individuals with HD.
Abstract:
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.
