Proteins involved in DNA repair, particularly mismatch repair, can modify the age at onset and rate of progression of Huntington disease (HD), probably by altering the rate of somatic expansion of CAG repeats in the huntingtin gene (HTT).The modulation of DNA repair factors, such as MSH3, FAN1, PMS2 and LIG1, has therapeutic potential in HD and other repeat expansion diseases.Nucleocytoplasmic transport is disrupted in HD by sequestration of nuclear pore components in HTT aggregates; modulation of nucleocytoplasmic transport is neuroprotective and might provide a novel therapeutic opportunity.Changes in cerebrospinal fluid and serum biomarkers, including neurofilament light chain and mutant HTT, are among the earliest detectable changes in HD and can predict disease onset and track progression.Intrathecally delivered non-allele-selective antisense oligonucleotides (ASOs) have successfully lowered HTT concentrations in the central nervous system of individuals with HD, and trials of allele-specific ASOs are under way.Gene-editing strategies for HTT lowering, including zinc finger proteins, transcription activator-like effector nucleases and CRISPR–Cas9, are currently in preclinical development, but need to be delivered via the injection of viral vectors, which can be challenging.
