Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment
Abstract
Genetic modifiers of Huntington's disease (HD) disease onset and progression implicate somatic instability (SI) of the expanded CAG repeat as a key pathogenic driver, with MSH3 emerging as a therapeutic target. Here, we generated a computational model that uses HD patient data to infer therapeutic effects of reducing SI and in parallel designed an artificial miRNA to lower MSH3 mRNA (miMSH3) after delivery with AAV-DB-3, a previously described medium spiny neuron (MSN)-targeting AAV capsid variant. AAV-DB-3.miMSH3 achieved 48-94% MSH3 mRNA reduction in MSNs of nonhuman primates (NHPs), which when applied to predictive modeling predicts 50-120 % slowing of HD progression as measured by change from baseline in the composite Unified Huntington Disease Rating Scale. Additionally, AAV-DB-3.miMSH3 reduced SI reduction by up to 46% in HdhQ111 mice. Cumulatively, the preclinical experimental data and the computational model support the translational potential of AAV-DB-3.miMSH3 as a disease-modifying therapy for HD.
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BibTeX
@article{simpson2026computational,
title = {{Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment}},
author = {Bryan P. Simpson and Paul T. Ranum and David E. Leib and Luis Tecedor and Ryan C. Giovenco and Icnelia Huerta-Ocampo and Amiel A. Hundley and Noah Smith and Christopher M. Fluta and Christopher P. Cali and Jamie Benoit and Jenna C. Soper and John Connelly and George J. Yohrling and P. Peter Ghoroghchian and Jang-Ho J. Cha and Beverly L. Davidson},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78769-2},
url = {https://www.nature.com/articles/s41467-026-78769-2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Computational modeling and preclinical evaluation support targeting somatic instability for Huntington’s disease treatment
AU - Bryan P. Simpson
AU - Paul T. Ranum
AU - David E. Leib
AU - Luis Tecedor
AU - Ryan C. Giovenco
AU - Icnelia Huerta-Ocampo
AU - Amiel A. Hundley
AU - Noah Smith
AU - Christopher M. Fluta
AU - Christopher P. Cali
AU - Jamie Benoit
AU - Jenna C. Soper
AU - John Connelly
AU - George J. Yohrling
AU - P. Peter Ghoroghchian
AU - Jang-Ho J. Cha
AU - Beverly L. Davidson
PY - 2026
DA - 2026/10/28
JO - Nature Communications
DO - 10.1038/s41467-026-78769-2
UR - https://www.nature.com/articles/s41467-026-78769-2
AB - Genetic modifiers of Huntington's disease (HD) disease onset and progression implicate somatic instability (SI) of the expanded CAG repeat as a key pathogenic driver, with MSH3 emerging as a therapeutic target. Here, we generated a computational model that uses HD patient data to infer therapeutic effects of reducing SI and in parallel designed an artificial miRNA to lower MSH3 mRNA (miMSH3) after delivery with AAV-DB-3, a previously described medium spiny neuron (MSN)-targeting AAV capsid variant. AAV-DB-3.miMSH3 achieved 48-94% MSH3 mRNA reduction in MSNs of nonhuman primates (NHPs), which when applied to predictive modeling predicts 50-120 % slowing of HD progression as measured by change from baseline in the composite Unified Huntington Disease Rating Scale. Additionally, AAV-DB-3.miMSH3 reduced SI reduction by up to 46% in HdhQ111 mice. Cumulatively, the preclinical experimental data and the computational model support the translational potential of AAV-DB-3.miMSH3 as a disease-modifying therapy for HD.
SN - 2041-1723
ER -