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.
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.
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S.J.T. receives grant funding for her HD research from the Medical Research Council UK, the Wellcome Trust, the Rosetrees Trust, NIHR North Thames Local Clinical Research Network, UK Dementia Research Institute, Wolfson Foundation for Neurodegeneration and the CHDI Foundation. This work was in part supported by the UK Dementia Research Institute, and research grant funding from the Wellcome Trust to S.J.T. and M.D.F. (ref 200181/Z/15/Z). M.D.F. received a PhD studentship from the Medical Research Council UK, a Clinical Lectureship from the UK Dementia Research Institute and Health Education England, and grant funding from the Rosetrees Trust and the Academy of Medical Sciences. C.A.R. receives funding for HD research from NIH and CHDI. This work was supported in part by NINDS 2R01NS086452-06 (GRANT12516201). E.J.W. receives funding from the Medical Research Council UK (Clinician Scientist Fellowship MR/M008592/1), CHDI Foundation, the Wellcome Trust (Wellcome Collaborative Award In Science 200181/Z/15/Z), Huntington’s Disease Society of America, the Hereditary Disease Foundation, the National Institute for Health Research Biomedical Research Centres funding scheme.
In the past two years S.J.T. has undertaken consultancy services, including advisory boards, with F. Hoffmann-La Roche Ltd, Ixitech Technologies, Takeda Pharmaceuticals International and Triplet therapeutics. All honoraria for these consultancies were paid to University College London, S.J.T.’s employer. Through the offices of UCL Consultants Ltd, a wholly owned subsidiary of University College London, S.J.T. has undertaken consultancy services for Alnylam Pharmaceuticals Inc., F. Hoffmann-La Roche Ltd, GSK, Heptares Therapeutics, LoQus therapeutics, Takeda Pharmaceuticals Ltd, TEVA Pharmaceuticals, Triplet therapeutics, UCB Pharma S.A., University College Irvine and Vertex Pharmaceuticals Incorporated. S.J.T. receives grant funding for her research from Takeda Pharmaceuticals and Cantervale Limited. C.A.R. is chair of the Research Advisory Board of the Huntington Study Group. Within the past two years, C.A.R. has consulted for Annexon, Roche, Sage and uniQure. C.A.R. receives funding for Huntington disease research from F. Hoffman-La Roche. Through UCL Consultants Ltd, a wholly owned subsidiary of University College London. E.J.W. has served on scientific advisory boards for F. Hoffmann–La Roche, Ionis, Mitoconix, Novartis, PTC Therapeutics, Shire, Takeda Pharmaceuticals and Wave Life Sciences. M.D.F. declares no competing interests.
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- Choreiform movements
Repetitive and rapid, jerky, involuntary movements.
- Somatic instability
Expansion or contraction of repeat units within a repetitive DNA tract, the rate of which is tissue-specific.
- RNA foci
Expanded RNA repeats that are retained in the nucleus, adopt unusual secondary structures, sequester RNA-binding proteins, and can become toxic to the cell.
- Repeat-associated non-ATG translation
A repeat-length-dependent process that enables translation initiation at non-canonical codons either within or adjacent to the expanded repeat tract.
Formed when one DNA strand is extruded from a CAG·CTG repeat region; intrastrand links then lead to the formation of a hairpin, with A–A or T–T base mispairing when the CAG or CTG strand is extruded, respectively.
- Lagging strand
The strand of nascent DNA that is synthesized in the opposite direction to the direction of the growing replication fork.
A small non-coding RNA molecule that functions in RNA silencing and post-transcriptional regulation of gene expression.
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Tabrizi, S.J., Flower, M.D., Ross, C.A. et al. Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol 16, 529–546 (2020). https://doi.org/10.1038/s41582-020-0389-4