July 29, 2026 —
Researchers at the University of Illinois Urbana-Champaign reported preclinical data showing that an AAV-delivered base editing strategy reduced toxic huntingtin protein fragments and improved disease-associated outcomes in mouse models of Huntington’s disease.
The findings were published in Nature Biomedical Engineering in a paper 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 the Department of Bioengineering at UIUC.
Huntington’s disease is a fatal inherited neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the huntingtin, or HTT, gene. Symptoms can include personality changes, unsteady gait, involuntary movements, slurred speech, and progressive functional decline.
Rather than shutting down HTT expression entirely, the UIUC team designed base editors to alter how the huntingtin protein is processed. The strategy targets HTT exon 13, which encodes proteolytic cleavage sites involved in the production of toxic N-terminal huntingtin fragments.
By disrupting the splice acceptor of exon 13, the base editing approach is intended to promote skipping of this small region and generate huntingtin isoforms that are more resistant to proteolytic cleavage. This could reduce formation of toxic fragments while avoiding complete loss of huntingtin protein function.
The researchers designed and screened more than 140 base editors to identify candidates that could target the exon of interest with minimal unintended effects. Lead editors were then delivered into the brains of mice carrying mutant HTT genes using AAV vectors.
In treated mice, the researchers observed reduced accumulation of toxic huntingtin fragments, fewer disease-associated symptoms, and less brain degeneration compared with untreated animals. These results support the concept that precise editing of HTT processing may offer a therapeutic path for Huntington’s disease.
The approach differs from gene-silencing strategies that aim to broadly lower huntingtin levels. Because normal huntingtin has important biological functions, selectively modifying the disease-driving processing step may offer a more targeted strategy if safety and efficacy can be confirmed in further studies.
Next steps include testing lead HTT exon 13-skipping editors in humanized mouse models to assess tolerability and determine whether editing lowers wild-type HTT below a tolerated threshold. The team also plans to evaluate target engagement and tolerability in large animals across multiple doses to define a therapeutic window.
The researchers are also exploring ways to refine delivery to the brain, including approaches that may be less invasive and less dependent on viral transport. While the work remains preclinical, the study highlights the growing potential of in vivo AAV-based gene editing for neurodegenerative diseases driven by toxic protein mechanisms.
