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Reducing Huntington’s-related repeat expansions in patient cells and in mice
Base editing of the pathogenic trinucleotide repeat expansions underlying Huntington’s disease and Friedreich’s ataxia introduces repeat interruptions that reduce somatic expansion in patient cells and mice.
To assess Cas-dependent off-target activity of CAG-CBE, we performed circularization for in vitro reporting of cleavage effects by sequencing (CIRCLE-seq) analysis on human genomic DNA (gDNA) from HEK293T cells using purified ribonucleoprotein complexes composed of Cas9-NG nuclease and sgCTG 69. Collectively, the data reveal that neonatal ICV injection of AAV9-CBE enables substantial transduction of HD-relevant tissues in humanized HD mice, significantly reducing the average size of pathogenic HTT CAG repeats by inducing synonymous CAG-to-CAA interruptions with proportionally few byproducts ( Supplementary Text, Fig. In contrast, the YG8s.300 and YG8s.800 mouse models of FRDA harbor a human FXN YAC transgene with ~300 and 800 GAA units, respectively, that undergo progressive instability starting at ~18 weeks of age that is biased toward expansion of repeats in somatic tissues, including the cortex, striatum and the liver, but not the tail 110, 111, 112.
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