Base Editing Strategy Alleviates Huntington’s Disease in Mice

According to at least one estimate, approximately 41,000 people in the United States have symptoms of Huntington’s disease, and more than 200,000 are at-risk of inheriting the disease. Symptoms of the neurodegenerative disorder, which is caused by a CAG expansion within exon 1 of the huntingtin gene, include personality changes, unsteady gait and involuntary movements, slurred speech, and more. Currently, there are multiple efforts underway to develop effective treatments, some of which are in clinical trials, that could slow or stop disease progression. 

One of those is an approach that uses in vivo base editing to precisely edit a portion of the gene that causes Huntington’s disease. When tested in mice, the CRISPR tool, which was designed by scientists at the University of Illinois Urbana-Champaign (UIUC), reduced toxic protein fragments and symptoms associated with the disease. Details of the method are published in a new Nature Biomedical Engineering paper aptly titled “In vivo CRISPR base editing for treatment of Huntington’s disease.” 

The work was led by Pablo Perez-Pinera, MD, PhD, and Thomas Gaj, PhD, both associate professors in UIUC’s department of bioengineering. Rather than using CRISPR to turn the Huntington gene off, the team designed base-editors that alter a specific point of the gene—the mutation that makes the Huntington protein prone to being cleaved into the toxic fragments that gradually kill brain cells. Specifically, the base editors that they used “generate proteolysis-resistant HTT isoforms by disrupting the splice acceptor of HTT exon 13, an exon that encodes critical proteolytic cleavage sites implicated in N-terminal fragment production,” they wrote in the paper. This change enables the cell’s machinery to skip that small section.

For the study, the scientists designed and screened more than 140 base editors to identify options that best targeted the exon of interest with the fewest unintended effects. They then injected them into the brains of mice with mutant HTT genes using AAVs as the delivery vehicle. Their analysis of the mice showed that those that received the treatment accumulated fewer toxic protein fragments, had fewer symptoms, and had less degeneration within the brain than untreated mice. 

As part of their next steps, the scientists plan to evaluate the lead HTT exon 13-skipping editors in humanized mice models to assess the tolerability of the treatment and determine whether editing reduces the wild-type HTT below a tolerated threshold. They also plan to evaluate “target engagement and tolerability in large animals across a range of doses to define the therapeutic window and guide future dose selection,” according to the paper.  

Other plans are to refine delivery of the base editors to the brain, to make it less invasive and less reliant on viruses for transport, said Kyrollos Shenouda, a graduate student at UIUC and one of the authors on the paper. “We’re also interested in adapting this approach to target other regions of the HTT gene to decrease other toxic aspects of the protein,” Shenouda said.

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