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CRISPR/Cas9-mediated Targeted Integration In Vivo Using a Homology-mediated End Joining-based Strategy
Published on: March 12, 2018
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 reduced mutant huntingtin protein levels and improved neurological symptoms in Huntington's disease (HD) mouse models. This therapy shows promise for treating this inherited neurodegenerative disorder.
Area of Science:
- Neuroscience
- Genetics
- Biotechnology
Background:
- Huntington's disease (HD) is an inherited neurodegenerative disorder.
- It is caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene.
- Currently, no approved disease-modifying therapies exist for HD.
Purpose of the Study:
- To develop and evaluate a pan-HTT-targeting CRISPR-Cas9 system for treating Huntington's disease.
- To assess the efficacy and safety of this gene-editing approach in preclinical models.
Main Methods:
- A CRISPR-Cas9 system targeting the huntingtin (HTT) gene was developed.
- The system was delivered to the striatum of R6/2 and YAC128 mouse models of HD using AAV5.
- Gene editing efficacy, behavioral outcomes, and neuropathological changes were assessed.
Main Results:
- The CRISPR-Cas9 system reduced mutant HTT mRNA and protein levels by 55-80% in HD mouse models.
- Targeting improved motor function, reduced anxiety-like behaviors, and mitigated weight loss and striatal atrophy.
- In a humanized mouse model, HTT protein was reduced without significant adverse behavioral effects, though neuroinflammation was observed.
Conclusions:
- The developed pan-HTT-targeting CRISPR-Cas9 system demonstrates significant therapeutic potential for Huntington's disease.
- This approach effectively reduces mutant HTT and ameliorates HD-related phenotypes in preclinical models.
- Further research is warranted to optimize the system and assess its long-term safety and tolerability.
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 adeno-associated virus serotype 5 (AAV5), lowered mutant HTT mRNA and protein by 55%-80% via its induction of frameshift-inducing insertion or deletion (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 of a newly developed pan-HTT-targeting Cas9 system to affect HD-related phenotypes across models and provide insights into its tolerability.
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01:21Huntington Disease l: Introduction
01:59CRISPR
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