Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Huntington disease (HD) is a neurodegenerative disease caused by CAG repeat expansion in the huntingtin gene ( HTT ) and involves a complex web of pathogenic mechanisms. Mutant HTT (mHTT) disrupts transcription, interferes with immune and mitochondrial function, and is aberrantly modified post-translationally. Evidence suggests that the mHTT RNA is toxic, and at the DNA level, somatic CAG repeat expansion in vulnerable cells influences the disease course. Genome-wide association studies have identified DNA repair pathways as modifiers of somatic instability and disease course in HD and other repeat expansion diseases. In animal models of HD, nucleocytoplasmic transport is disrupted and its restoration is neuroprotective. Novel cerebrospinal fluid (CSF) and plasma biomarkers are among the earliest detectable changes in individuals with premanifest HD and have the sensitivity to detect therapeutic benefit. Therapeutically, the first human trial of an HTT -lowering antisense oligonucleotide successfully, and safely, reduced the CSF concentration of mHTT in individuals with HD. A larger trial, powered to detect clinical efficacy, is underway, along with trials of other HTT-lowering approaches. In this Review, we discuss new insights into the molecular pathogenesis of HD and future therapeutic strategies, including the modulation of DNA repair and targeting the DNA mutation itself. In this Review, Tabrizi et al. discuss new insights into the molecular pathogenesis of Huntington disease and outline potential therapeutic strategies, which could include the modulation of DNA repair processes. Key points 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 oligonucleo