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Updated: May 29, 2026
Efficient and Scalable Production of Full-length Human Huntingtin Variants in Mammalian Cells using a Transient Expression System
Published on: December 10, 2021
Viral-mediated overexpression of mutant huntingtin to model HD in various species
1Atomic Energy Commission (CEA), Institute of Biomedical Imaging (I2BM), Molecular Imaging Research Center (MIRCen), Fontenay-aux-Roses, France.
Insights
Viral vector gene transfer enables new Huntington's disease (HD) models. This approach allows targeted delivery of the mutant huntingtin (Htt) gene, aiding research into HD pathogenesis and therapeutic development.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by CAG repeat expansion in the huntingtin (Htt) gene.
- Current treatments for HD are unavailable, largely due to a lack of effective disease models.
- Understanding HD pathogenesis is crucial for developing targeted therapies.
Purpose of the Study:
- To highlight advances in modeling Huntington's disease using viral vector gene transfer.
- To demonstrate the utility of viral vectors for targeted gene delivery in HD research.
- To showcase the potential of these models for pre-clinical therapeutic development.
Main Methods:
- Utilizing adeno-associated virus (AAV) or lentivirus vectors for gene transfer.
- Overexpressing mutant human huntingtin (Htt) in specific brain regions, such as the striatum.
- Employing rodent and primate models to study disease progression.
Main Results:
- Viral vector-mediated overexpression of mutant Htt in rodents induces progressive neurodegeneration resembling HD.
- This method allows for targeted delivery of the disease-causing gene to specific tissues.
- The models facilitate experimental analysis of pathological processes.
Conclusions:
- Viral vector gene transfer offers a flexible and effective approach for modeling Huntington's disease.
- These advanced models are instrumental in understanding HD pathogenesis.
- Targeted gene delivery via viral vectors opens new avenues for pre-clinical therapeutic development in HD.
Abstract:
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expansion of CAG repeats in the huntingtin (Htt) gene. Despite intensive efforts devoted to investigating the mechanisms of its pathogenesis, effective treatments for this devastating disease remain unavailable. The lack of suitable models recapitulating the entire spectrum of the degenerative process has severely hindered the identification and validation of therapeutic strategies. The discovery that the degeneration in HD is caused by a mutation in a single gene has offered new opportunities to develop experimental models of HD, ranging from in vitro models to transgenic primates. However, recent advances in viral-vector technology provide promising alternatives based on the direct transfer of genes to selected sub-regions of the brain. Rodent studies have shown that overexpression of mutant human Htt in the striatum using adeno-associated virus or lentivirus vectors induces progressive neurodegeneration, which resembles that seen in HD. This article highlights progress made in modeling HD using viral vector gene transfer. We describe data obtained with of this highly flexible approach for the targeted overexpression of a disease-causing gene. The ability to deliver mutant Htt to specific tissues has opened pathological processes to experimental analysis and allowed targeted therapeutic development in rodent and primate pre-clinical models.
