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Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Antisense oligonucleotide-mediated MSH3 suppression reduces somatic CAG repeat expansion in Huntington's disease
Emma L Bunting1, Jasmine Donaldson1, Sarah A Cumming2
1Huntington's Disease Centre and Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology and UK Dementia Research Institute, UCL, London, UK.
Insights
Antisense oligonucleotides targeting MSH3 protein effectively reduced its levels and halted the expansion of CAG repeats in Huntington's disease (HD) patient-derived neurons. This approach shows therapeutic potential for treating HD by stabilizing the huntingtin (HTT) gene.
Area of Science:
- Genetics
- Neuroscience
- Molecular Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by expanded CAG repeats in the huntingtin (HTT) gene.
- Somatic expansion of these CAG repeats drives HD onset and progression.
- The DNA mismatch repair protein MSH3 plays a key role in this CAG repeat expansion process.
Purpose of the Study:
- To investigate the therapeutic potential of targeting MSH3 to reduce somatic CAG repeat expansion in Huntington's disease.
- To evaluate the efficacy and safety of an MSH3-targeting antisense oligonucleotide (ASO) in patient-derived cells and a mouse model.
Main Methods:
- Utilized induced pluripotent stem cell (iPSC)-derived striatal neurons from an HD patient with 125 HTT CAG repeats.
- Administered MSH3-targeting antisense oligonucleotides (ASOs) to reduce MSH3 levels.
- Performed bulk RNA sequencing to assess the safety profile of MSH3 reduction.
- Created and tested a human MSH3 knock-in mouse model.
Main Results:
- ASO treatment effectively reduced MSH3 levels in a dose-dependent manner in HD patient-derived neurons.
- MSH3 reduction led to a significant stalling of HTT CAG repeat expansion.
- Bulk RNA sequencing indicated a safe profile for MSH3 reduction, even at >95% knockdown.
- ASO treatment successfully reduced human MSH3 levels in vivo in a knock-in mouse model.
Conclusions:
- ASO-mediated MSH3 reduction is a promising therapeutic strategy for preventing HTT CAG repeat expansion in Huntington's disease.
- Targeting MSH3 offers a potential pathway to slow or halt HD progression.
Abstract:
Expanded CAG alleles in the huntingtin (HTT) gene that cause the neurodegenerative disorder Huntington's disease (HD) are genetically unstable and continue to expand somatically throughout life, driving HD onset and progression. MSH3, a DNA mismatch repair protein, modifies HD onset and progression by driving this somatic CAG repeat expansion process. MSH3 is relatively tolerant of loss-of-function variation in humans, making it a potential therapeutic target. Here, we show that an MSH3-targeting antisense oligonucleotide (ASO) effectively engaged with its RNA target in induced pluripotent stem cell (iPSC)-derived striatal neurons obtained from a patient with HD carrying 125 HTT CAG repeats (the 125 CAG iPSC line). ASO treatment led to a dose-dependent reduction of MSH3 and subsequent stalling of CAG repeat expansion in these striatal neurons. Bulk RNA sequencing revealed a safe profile for MSH3 reduction, even when reduced by >95%. Maximal knockdown of MSH3 also effectively slowed CAG repeat expansion in striatal neurons with an otherwise accelerated expansion rate, derived from the 125 CAG iPSC line where FAN1 was knocked out by CRISPR-Cas9 editing. Last, we created a knock-in mouse model expressing the human MSH3 gene and demonstrated effective in vivo reduction in human MSH3 after ASO treatment. Our study shows that ASO-mediated MSH3 reduction can prevent HTT CAG repeat expansion in HD 125 CAG iPSC-derived striatal neurons, highlighting the therapeutic potential of this approach.
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