Abstract

Expanded CAG/CTG repeats, including Huntington’s disease, myotonic dystrophy, and several spinocerebellar ataxias, remain without a disease altering treatment, which represents an important unmet medical need. Although the clinical manifestation varies greatly between these diseases, their underlying cause is the same: the expansion of a CAG/CTG tandem repeat at a specific locus in the genome. In all cases, the longer the repeat tract, the more severe the disease phenotypes. Thus, an attractive hypothesis is that contracting the repeat tract to non-pathologic sizes will remove the underlying cause of the disease and thereby may slow, stop, or prevent disease progression. Here I present our work on developing a gene editing approach to contract expanded repeat tracts. It relies on a mutated Cas9 (D10A), which turns the enzyme into a nickase. Expressing the Cas9 nickase together with a guide RNA that targets it to the repeat tract itself efficiently contracts expanded repeats at multiple loci and in multiple cell types. The approach does not appear to induce a significant number of off-target mutations or on-target rearrangements and does not change the size of tracts within the non-pathogenic range. Together this approach may represent a novel therapeutic avenue worth translating into the clinic.