I05 CRISPR-Cas9 nickase-mediated gene editing to treat Huntington’s disease

Expanded CAG/CTG repeats cause at least 15 different diseases, including Huntington’s disease. It affects about 1 in 10,000 people world-wide and remains without an effective treatment. Thus, the development of new therapies remains a major unmet medical need. The size of the repeat tract scales with disease severity, therefore, inducing CAG/CTG repeat contractions is an attractive treatment avenue. Our lab has developed the first method capable of achieving this. Here, we show that the CRISPR-Cas9 nickase targeted to the CAG/CTG repeat itself leads to efficient contractions in multiple cellular systems, amongst them, in HD iPSC-derived neurons and astrocytes. Indeed, we found that this approach is specific for the expanded allele and off-targets mutations remained undetected using the whole genome sequencing. This indicates that our approach is a safe for further in vivo work.