Seminario INCyL – Álvaro Murillo

Expanded CAG/CTG repeats cause over 15 different diseases that all remain without a
disease-modifying treatment. Because repeat length accounts for most of the variation
in disease severity, contracting them presents an attractive therapeutic avenue. Here, we
show that the CRISPR-Cas9 nickase targeted to CAG/CTG repeats leads to efficient
contractions in Huntington’s disease patient-derived neurons and astrocytes, and in
myotonic dystrophy type 1 patient-derived neurons. The approach is allele-selective and
free of detectable off-target mutations. Striatal injection of the Cas9 nickase in a mouse
model for Huntington’s disease using adeno-associated viral vectors led to contractions
in over half of the infected cells. One month after injection, Huntington’s disease mice
displayed gross locomotor skills that were not significantly different from that of their wild
type littermates. Contractions were accompanied by improvements in molecular
pathology. Our results provide the proof-of-concept that correction of CAG/CTG repeats
can improve Huntington’s disease phenotypes in vivo.