Inhibiting Cytosine-Adenine-Guanine (CAG) repeat expansions as a therapeutic strategy for Huntington's disease.

Huntington's Disease (HD) became the first disease mapped to a single chromosome and associated with mutations in the huntingtin (HTT) gene, specifically expansions in the trinucleotide cytosine-adenine-guanine (CAG) within exon 1. The onset and progression of disease has been linked, inversely, to the inherited CAG repeat length in the mutated allele but also to an ongoing somatic expansion. However, HD remains an unmet medical need. A rational but not yet successful therapeutic approach has been to inhibit the mutant HTT mRNA/protein although recent trials have shown signs of early promise. Somatic expansion of the CAG repeat length, beyond the inherited length, has been associated with hastening the onset of symptoms compared to that predicted from the germline length. Targeting somatic CAG repeat expansion as a therapeutic has been challenging due to several factors including difficulty in modeling this phenomenon preclinically, capturing somatic expansion in post-mortem brain tissue from HD patients and the relative lack of specific targets. Moreover, more recent GWAS data also show that many of the gene loci which influence either age of onset or clinical landmarks exhibit complexity such as cell-specific effects, influence of non-canonical sequences and a lack of concordance between affecting somatic expansion and clinical landmarks. This complicates identifying appropriate targets for drug discovery programs including the DNA mismatch repair proteins. After briefly reviewing the approaches targeting the mutant HTT we will discuss possible paths forward to adjudicate the clinical data on somatic expansion with a focus on next steps for drug discovery.