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Treatment of Huntington's disease with a pan-HTT-targeting CRISPR nuclease
Katherine Tan1, Daniela Del Bosque Siller2, Alisha Y Xiong2
1Department of Bioengineering, Grainger College of Engineering, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA.
Insights
A novel CRISPR-Cas9 gene editing system effectively targets and reduces mutant huntingtin protein in mouse models of Huntington's disease (HD). This approach shows promise for treating HD by improving motor function and reducing disease symptoms.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a fatal, inherited neurodegenerative disorder.
- It results from a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, producing a toxic mutant protein.
- Currently, no approved disease-modifying therapies exist for HD.
Purpose of the Study:
- To develop and evaluate a CRISPR-Cas9 gene editing system targeting the huntingtin (HTT) gene for potential Huntington's disease therapy.
- To assess the efficacy and safety of this system in preclinical mouse models of HD.
Main Methods:
- AAV5-mediated delivery of a pan-HTT-targeting CRISPR-Cas9 system to the striatum of R6/2 and YAC128 mouse models.
- Analysis of mutant HTT mRNA and protein levels, motor function, behavioral deficits, and neuropathological hallmarks.
- Evaluation in Hu21/21 mice carrying the human wild-type HTT gene to assess tolerability and potential off-target effects.
Main Results:
- The CRISPR-Cas9 system reduced mutant HTT mRNA and protein by 55-80% in HD mouse models.
- Targeting improved motor coordination, locomotor activity, and reduced anxiety-like behaviors.
- Significant reductions in clasping, weight loss, striatal atrophy, and intranuclear inclusions were observed.
- In Hu21/21 mice, HTT protein was reduced by 44% without measurable behavioral deficits or neuronal damage, though neuroinflammation was noted.
Conclusions:
- A novel pan-HTT-targeting CRISPR-Cas9 system demonstrates significant therapeutic potential for Huntington's disease.
- The system effectively reduces mutant HTT and ameliorates key HD phenotypes in mouse models.
- Further research is warranted to explore its safety and efficacy, particularly regarding neuroinflammation.
Abstract:
Huntington's disease (HD) is an inherited neurodegenerative disorder caused by an expansion of a CAG trinucleotide repeat in the huntingtin (HTT) gene, which leads to a mutant protein that destroys neurons in the brain. Despite intense effort, there remains no approved disease-modifying therapy for HD. Here we develop a pan-HTT-targeting CRISPR-Cas9 system that, when delivered to the striatum of R6/2 and YAC128 mice by AAV5, lowered mutant HTT mRNA and protein by 55-80% via its induction of frameshift-inducing indel mutations in HTT exon 1. Cas9 targeting improved motor coordination and locomotor activity, decreased anxiety-like deficits, reduced clasping and weight loss, limited striatal atrophy, and decreased the formation of intranuclear inclusions immunoreactive for the mutant HTT protein. In Hu21/21 mice, which carry the wild-type human HTT gene in lieu of the mouse ortholog, Cas9 lowered the HTT protein by 44% but induced no measurable behavioral deficits and had no adverse effect on neuronal viability, though its targeting was associated with neuroinflammation. Altogether, our results demonstrate the ability for a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provides insights into its tolerability.
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