Expanded CAG/CTG repeats resist gene silencing mediated by targeted epigenome editing.

Expanded CAG/CTG repeat disorders affect over 1 in 2500 individuals worldwide. Potential therapeutic avenues include gene silencing and modulation of repeat instability. However, there are major mechanistic gaps in our understanding of these processes, which prevent the rational design of an efficient treatment.

GFP Reporters to Monitor Instability and Expression of Expanded CAG/CTG Repeats.

Expanded CAG/CTG repeats are genetically unstable and, upon expression, cause neurological and neuromuscular diseases. The molecular mechanisms of repeat instability and expression remain poorly understood despite their importance for the pathogenesis of a family of 14 devastating human diseases. This is in part because conventional assays are tedious and time-consuming.

Contracting CAG/CTG repeats using the CRISPR-Cas9 nickase.

CAG/CTG repeat expansions cause over 13 neurological diseases that remain without a cure. Because longer tracts cause more severe phenotypes, contracting them may provide a therapeutic avenue. No currently known agent can specifically generate contractions.