Base Editing Protects Brains From Mutant Huntingtin

Rather than correcting the expanded CAG repeat that causes Huntington’s disease, the researchers edited the splice acceptor of HTT exon 13. This caused full or partial exon skipping. The partial event removed 39 bases while preserving the reading frame and eliminating a site where proteolysis can generate aggregation-prone N-terminal huntingtin fragments.

For in vivo testing, a near-PAMless SpRY adenine base editor was divided between two AAV9 vectors and injected bilaterally into the striatum of one-month-old YAC128 mice. At 12 months, editing reached approximately 16 per cent in bulk striatal tissue and produced nine per cent exon skipping. Treated mice had 60 per cent fewer N-terminal huntingtin fragments and 63 per cent fewer cells containing mutant huntingtin inclusions. They also showed improved grip strength, rotarod performance and limb clasping, while striatal and cortical volume loss was reduced.

The editor also produced bystander substitutions. Moreover, YAC128 mice retain endogenous mouse Hdh and lack a healthy human HTT allele, limiting assessment of consequences for normal huntingtin function. Specificity testing was restricted to predicted off-target sites.

The study was led by Shraddha Shirguppe, Michael Gapinske, Devyani Swami, Thomas Gaj and Pablo Perez-Pinera at the University of Illinois Urbana-Champaign. It was published in Nature Biomedical Engineering on 29 July 2026.