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Updated: Mar 20, 2026
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Selective targeting of mutant huntingtin intron 1 improves rescue provided by antisense oligonucleotides in
Robert M Bragg1, Christian Landles2, Edward J Smith2
1Department of Neurology, University of Washington, Seattle, WA 98104, USA.
Insights
Huntington's disease therapies can be improved by targeting the toxic HTT1a protein. An allele-selective antisense oligonucleotide effectively reduced HTT1a, mitigating key disease pathologies in mice.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is caused by a CAG expansion in the huntingtin (HTT) gene, leading to toxic gain of function.
- Somatic instability of the mutant HTT (mHTT) CAG repeat contributes to HD pathogenesis.
- Alternative HTT pre-mRNA processing generates the highly toxic HTT1a transcript.
Purpose of the Study:
- To compare allele-selective versus non-allele-selective lowering of mHTT using antisense oligonucleotides (ASOs) in a mouse model of HD.
- To evaluate the efficacy and safety of a novel mutant-specific ASO (MutASO) targeting HTT1a.
Main Methods:
- Developed a MutASO targeting Htt intron 1 for allele-selective reduction of mHTT and HTT1a.
- Administered MutASO and a pan-allele-targeting ASO (PanASO) to heterozygous HttQ111 mice.
- Assessed aggregate formation and transcriptional dysregulation in mouse brains.
Main Results:
- MutASO selectively reduced mutant full-length HTT and HTT1a in Q111 mouse brains.
- MutASO treatment eliminated aggregate formation and protected against transcriptional dysregulation.
- Compared to PanASO, MutASO demonstrated superior efficacy in mitigating HD-related pathologies.
Conclusions:
- HTT1a may disproportionately contribute to HD pathogenesis, including aggregate formation and transcriptional issues.
- Targeting HTT1a with allele-selective ASOs represents a promising therapeutic strategy for Huntington's disease.
- Lowering HTT1a levels could be a key benefit in developing future HD therapeutics.
Abstract:
Huntington's disease (HD) arises from the toxic gain of function caused by a CAG expansion in the coding region of the huntingtin (HTT) gene. HD is increasingly appreciated to emerge from multiple pathogenic processes, including somatic instability in mutant HTT's (mHTT) CAG repeat tract, which leads to diverse deleterious consequences. These include the alternative processing of HTT pre-mRNA to generate the HTT1a transcript that encodes the very toxic mHTT isoform referred to as HTT1a. We set out to compare the efficacy and safety of allele-selective lowering of mHTT with those of non-allele-selective lowering using antisense oligonucleotides (ASOs) in heterozygous HttQ111 (Q111) mice. We developed a mutant-specific ASO (MutASO) targeting Htt intron 1 that selectively reduced mutant full-length HTT, as well as HTT1a, in the brains of Q111 mice. Compared with the rescue provided by a panallele-targeting ASO (PanASO) that lowers wild-type HTT and full-length mHTT (sparing HTT1a), the MutASO essentially eliminated aggregate formation and provided marked protection from transcriptional dysregulation in HD knockin mice. Thus, by targeting the ASO to the region upstream of the cryptic polyadenylation sites required to generate the HTT1a transcript, our allele-selective MutASO potently reduced HTT1a transcript and protein levels. Our findings suggest that HTT1a may have a disproportionate impact on aggregate formation and transcriptional dysregulation and that lowering the levels of HTT1a could provide benefit when designing HTT-lowering-based therapeutic strategies for HD.
