BioTechniques News
Tristan Free
Researchers have designed and delivered a gene-editing tool to a mouse model of Huntington’s disease, successfully reducing accumulation of toxic protein fragments and degeneration in the brain.
Researchers at the University of Illinois Urbana-Champaign (IL, USA) have developed a base-editing treatment that, when injected into the brains of mice, reduced Huntington’s disease symptoms, including a reduction in toxic protein accumulation and degeneration in the brain. This base-editing approach not only shows promise for Huntington’s disease, but other genetic conditions as well, without completely inactivating a gene or directly correcting a mutation.
An inherited neurodegenerative disorder, Huntington’s disease is caused by an expanded CAG trinucleotide repeat in exon1 of the huntingtin (HTT) gene. While the full pathogenic mechanism of the condition is still to be confirmed, this extension results in the production of a mutant protein vulnerable to cleavage, which releases N-terminal fragments that form aggregates in the brain and contribute to progressive neuronal loss. With no cure and the only existing treatments offering symptomatic relief, the development of new interventions is essential.
That’s why the research group, led by bioengineering professors Pablo Perez-Pinera and Thomas Gaj, set out to develop CRISPR base editors that generate HTT proteins resistant to proteolytic cleavage. To accomplish this, the team screened over 140 base editor variants, all of which target splicing elements in HTT, to find those able to disrupt the splice acceptor of exon 13, a critical component of the proteolytic cleavage site implicated in N-terminal fragment production. By converting a single nucleotide to another without cutting the double-stranded DNA, these base editors ultimately lead the cellular machinery reading the gene to skip exon 13, producing a protein that lacks the troublesome cleavage site.
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“Our base editors were developed to target the region of HTT that, when cleaved, can initiate the chain of events that leads to the toxic fragments. The result is that instead of turning the protein off completely, we alter how the gene is read so that the most damaging protein fragments are not produced,” Gaj explained.
The most successful base editors, with the fewest unintended effects, were then injected into the striatum of a Huntington’s disease mouse model. Those mice that received the base-editing treatment showed less toxic protein fragment formation and accumulation, attenuated brain atrophy and improved functional deficits in comparison to untreated mice.
“This approach not only shows that base editors have the potential to be used for Huntington’s disease, it also opens the door to a new kind of potential treatment for other genetic conditions,” Gaj concluded. “This study helps to show that treating genetic diseases can be done without inactivating a gene or directly correcting a mutation. Sometimes, it is possible to implement modifications to change how proteins function and that could be sufficient to protect the body from further damage.”
In future, the team plans to refine base-editor delivery to the brain, making it less invasive and finding alternative vectors. They are also interested in using this approach to target other regions of HTT to reduce the resulting protein’s toxicity.
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