Engineered Nucleases and Trinucleotide Repeat Diseases

Tandem repeats are consecutively repeated sets of nucleotides that mutate by the addition or loss of one or more repeat units. Tandem repeats can modulate gene function and heritable traits in a number of species including human. Mutations at a subset of repeats, most of which are trinucleotide repeats, trigger devastating human neurological and skeletal disorders. In particular, at least a dozen neurological disorders share a common etiology-the expansion of a CAG repeat tract from less than 30 units, to pathogenic lengths of up to hundreds and sometimes thousands of copies. These repeats are attractive targets for therapy because they underlie several disorders, but at the same time they are challenging to attack. Here we describe studies from our lab and others that have exploited engineered nucleases to target or disrupt disease-causing CAG repeats. We discuss the current challenges with this therapeutic approach and highlight the use of next-generation sequencing as a powerful tool to measure repeat mutation and the efficacy of nuclease-mediated genome editing.