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  • Review Article
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Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities

Nature Reviews Neurology volume 16, pages 529–546 (2020)Cite this article

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Abstract

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.

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 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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Fig. 1: The potential roles of DNA repair Huntington disease modifiers in somatic instability.
Fig. 2: The nuclear transport cycle is disrupted by sequestration of RanGAP1 and nucleoporins in mutant huntingtin aggregates.
Fig. 3: Therapeutic methods for lowering huntingtin expression.
Fig. 4: Phase I/IIa clinical trial of the HTTRx antisense oligonucleotide.

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References

  1. Bates, G. P. et al. Huntington disease. Nat. Rev. Dis. Primers 1, 1–21 (2015).

    Google Scholar 

  2. Paulson, H. Repeat expansion diseases. Handb. Clin. Neurol. 147, 105–123 (2018).

    PubMed  PubMed Central  Google Scholar 

  3. Evans, S. J. et al. Prevalence of adult Huntington’s disease in the UK based on diagnoses recorded in general practice records. J. Neurol. Neurosurg. Psychiatry 84, 1156–1160 (2013).

    PubMed  Google Scholar 

  4. Langbehn, D. R., Hayden, M. R. & Paulsen, J. S. CAG-repeat length and the age of onset in Huntington disease (HD): a review and validation study of statistical approaches. Am. J. Med. Genet. B Neuropsychiatr. Genet. 153b, 397–408 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Ross, C. A. et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat. Rev. Neurol. 10, 204–216 (2014).

    CAS  PubMed  Google Scholar 

  6. Palidwor, G. A. et al. Detection of alpha-rod protein repeats using a neural network and application to huntingtin. PLoS Comput. Biol. 5, e1000304 (2009).

    PubMed  PubMed Central  Google Scholar 

  7. Tartari, M. et al. Phylogenetic comparison of huntingtin homologues reveals the appearance of a primitive polyQ in sea urchin. Mol. Biol. Evol. 25, 330–338 (2008).

    CAS  PubMed  Google Scholar 

  8. Zheng, Z., Li, A., Holmes, B. B., Marasa, J. C. & Diamond, M. I. An N-terminal nuclear export signal regulates trafficking and aggregation of huntingtin (Htt) protein exon 1. J. Biol. Chem. 288, 6063–6071 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Bessert, D. A., Gutridge, K. L., Dunbar, J. C. & Carlock, L. R. The identification of a functional nuclear localization signal in the Huntington disease protein. Brain Res. Mol. Brain Res 33, 165–173 (1995).

    CAS  PubMed  Google Scholar 

  10. Xia, J., Lee, D. H., Taylor, J., Vandelft, M. & Truant, R. Huntingtin contains a highly conserved nuclear export signal. Hum. Mol. Genet. 12, 1393–1403 (2003).

    CAS  PubMed  Google Scholar 

  11. Nasir, J. et al. Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 (1995).

    CAS  PubMed  Google Scholar 

  12. Zeitlin, S., Liu, J. P., Chapman, D. L., Papaioannou, V. E. & Efstratiadis, A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington’s disease gene homologue. Nat. Genet. 11, 155–163 (1995).

    CAS  PubMed  Google Scholar 

  13. Saudou, F. & Humbert, S. The biology of huntingtin. Neuron 89, 910–926 (2016).

    CAS  PubMed  Google Scholar 

  14. Rosas, H. D. et al. Cerebral cortex and the clinical expression of Huntington’s disease: complexity and heterogeneity. Brain 131, 1057–1068 (2008).

    PubMed  Google Scholar 

  15. Johnson, E. B. et al. Dynamics of cortical degeneration over a decade in Huntington’s disease. Preprint at bioRxiv https://doi.org/10.1101/537977 (2019).

    Article  Google Scholar 

  16. Mann, D. M., Oliver, R. & Snowden, J. S. The topographic distribution of brain atrophy in Huntington’s disease and progressive supranuclear palsy. Acta Neuropathol. 85, 553–559 (1993).

    CAS  PubMed  Google Scholar 

  17. Heinsen, H. et al. Cortical and striatal neurone number in Huntington’s disease. Acta Neuropathol. 88, 320–333 (1994).

    CAS  PubMed  Google Scholar 

  18. Han, I., You, Y., Kordower, J. H., Brady, S. T. & Morfini, G. A. Differential vulnerability of neurons in Huntington’s disease: the role of cell type-specific features. J. Neurochem. 113, 1073–1091 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Ehrnhoefer, D. E., Sutton, L. & Hayden, M. R. Small changes, big impact: posttranslational modifications and function of huntingtin in Huntington disease. Neuroscientist 17, 475–492 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Hensman Moss, D. J. et al. Huntington’s disease blood and brain show a common gene expression pattern and share an immune signature with Alzheimer’s disease. Sci. Rep. 7, 44849 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hodges, A. et al. Regional and cellular gene expression changes in human Huntington’s disease brain. Hum. Mol. Genet. 15, 965–977 (2006).

    CAS  PubMed  Google Scholar 

  22. Pouladi, M. A., Morton, A. J. & Hayden, M. R. Choosing an animal model for the study of Huntington’s disease. Nat. Rev. Neurosci. 14, 708–721 (2013).

    CAS  PubMed  Google Scholar 

  23. Ramaswamy, S., McBride, J. L. & Kordower, J. H. Animal models of Huntington’s disease. ILAR J. 48, 356–373 (2007).

    CAS  PubMed  Google Scholar 

  24. Li, X. J. & Li, S. Large animal models of Huntington’s disease. Curr. Top. Behav. Neurosci. 22, 149–160 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    CAS  PubMed  Google Scholar 

  26. Hoffner, G., Island, M. L. & Djian, P. Purification of neuronal inclusions of patients with Huntington’s disease reveals a broad range of N-terminal fragments of expanded huntingtin and insoluble polymers. J. Neurochem. 95, 125–136 (2005).

    CAS  PubMed  Google Scholar 

  27. Cooper, J. K. et al. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum. Mol. Genet. 7, 783–790 (1998).

    CAS  PubMed  Google Scholar 

  28. Ross, C. A. Intranuclear neuronal inclusions: a common pathogenic mechanism for glutamine-repeat neurodegenerative diseases? Neuron 19, 1147–1150 (1997).

    CAS  PubMed  Google Scholar 

  29. Davies, S. W. et al. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions? Lancet 351, 131–133 (1998).

    CAS  PubMed  Google Scholar 

  30. Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    CAS  PubMed  Google Scholar 

  31. Arrasate, M., Mitra, S., Schweitzer, E. S., Segal, M. R. & Finkbeiner, S. Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death. Nature 431, 805–810 (2004).

    CAS  PubMed  Google Scholar 

  32. Slow, E. J. et al. Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc. Natl Acad. Sci. USA 102, 11402–11407 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Pieri, L., Madiona, K., Bousset, L. & Melki, R. Fibrillar α-synuclein and huntingtin exon 1 assemblies are toxic to the cells. Biophys. J. 102, 2894–2905 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Nucifora, L. G. et al. Identification of novel potentially toxic oligomers formed in vitro from mammalian-derived expanded huntingtin exon-1 protein. J. Biol. Chem. 287, 16017–16028 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Lajoie, P. & Snapp, E. L. Formation and toxicity of soluble polyglutamine oligomers in living cells. PLoS ONE 5, e15245 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Nagai, Y. et al. A toxic monomeric conformer of the polyglutamine protein. Nat. Struct. Mol. Biol. 14, 332–340 (2007).

    CAS  PubMed  Google Scholar 

  37. Miller, J. et al. Identifying polyglutamine protein species in situ that best predict neurodegeneration. Nat. Chem. Biol. 7, 925–934 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Sahl, S. J., Weiss, L. E., Duim, W. C., Frydman, J. & Moerner, W. E. Cellular inclusion bodies of mutant huntingtin exon 1 obscure small fibrillar aggregate species. Sci. Rep. 2, 895 (2012).

    PubMed  PubMed Central  Google Scholar 

  39. Leitman, J., Ulrich Hartl, F. & Lederkremer, G. Z. Soluble forms of polyQ-expanded huntingtin rather than large aggregates cause endoplasmic reticulum stress. Nat. Commun. 4, 2753 (2013).

    PubMed  Google Scholar 

  40. Takahashi, T. et al. Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Hum. Mol. Genet. 17, 345–356 (2008).

    CAS  PubMed  Google Scholar 

  41. Legleiter, J. et al. Mutant huntingtin fragments form oligomers in a polyglutamine length-dependent manner in vitro and in vivo. J. Biol. Chem. 285, 14777–14790 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Ast, A. et al. mHTT seeding activity: a marker of disease progression and neurotoxicity in models of Huntington’s disease. Mol. Cell 71, 675–688.e6 (2018).

    CAS  PubMed  Google Scholar 

  43. Sathasivam, K. et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc. Natl Acad. Sci. USA 110, 2366–2370 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sieradzan, K. A. et al. Huntington’s disease intranuclear inclusions contain truncated, ubiquitinated huntingtin protein. Exp. Neurol. 156, 92–99 (1999).

    CAS  PubMed  Google Scholar 

  45. Wang, C. E. et al. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington’s disease. Hum. Mol. Genet. 17, 2738–2751 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Castiglioni, V., Onorati, M., Rochon, C. & Cattaneo, E. Induced pluripotent stem cell lines from Huntington’s disease mice undergo neuronal differentiation while showing alterations in the lysosomal pathway. Neurobiol. Dis. 46, 30–40 (2012).

    CAS  PubMed  Google Scholar 

  47. HD iPSC Consortium. Induced pluripotent stem cells from patients with Huntington’s disease show CAG-repeat-expansion-associated phenotypes. Cell Stem Cell 11, 264–278 (2012).

    Google Scholar 

  48. Yang, W., Dunlap, J. R., Andrews, R. B. & Wetzel, R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum. Mol. Genet. 11, 2905–2917 (2002).

    CAS  PubMed  Google Scholar 

  49. Monsellier, E., Bousset, L. & Melki, R. α-Synuclein and huntingtin exon 1 amyloid fibrils bind laterally to the cellular membrane. Sci. Rep. 6, 19180 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Costanzo, M. et al. Transfer of polyglutamine aggregates in neuronal cells occurs in tunneling nanotubes. J. Cell Sci. 126, 3678–3685 (2013).

    CAS  PubMed  Google Scholar 

  51. Herrera, F., Tenreiro, S., Miller-Fleming, L. & Outeiro, T. F. Visualization of cell-to-cell transmission of mutant huntingtin oligomers. PLoS Curr. 3, RRN1210 (2011).

    PubMed  PubMed Central  Google Scholar 

  52. Babcock, D. T. & Ganetzky, B. Transcellular spreading of huntingtin aggregates in the Drosophila brain. Proc. Natl Acad. Sci. USA 112, E5427–E5433 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Pearce, M. M. P., Spartz, E. J., Hong, W., Luo, L. & Kopito, R. R. Prion-like transmission of neuronal huntingtin aggregates to phagocytic glia in the Drosophila brain. Nat. Commun. 6, 6768 (2015).

    CAS  PubMed  Google Scholar 

  54. Pecho-Vrieseling, E. et al. Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons. Nat. Neurosci. 17, 1064–1072 (2014).

    CAS  PubMed  Google Scholar 

  55. Kovacs, G. G. & Budka, H. Prion diseases: from protein to cell pathology. Am. J. Pathol. 172, 555–565 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cicchetti, F. et al. Mutant huntingtin is present in neuronal grafts in Huntington disease patients. Ann. Neurol. 76, 31–42 (2014).

    CAS  PubMed  Google Scholar 

  57. Lin, J. T. et al. Regulation of feedback between protein kinase A and the proteasome system worsens Huntington’s disease. Mol. Cell Biol. 33, 1073–1084 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Cortes, C. J. & La Spada, A. R. The many faces of autophagy dysfunction in Huntington’s disease: from mechanism to therapy. Drug Discov. Today 19, 963–971 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Ravikumar, B. et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat. Genet. 36, 585–595 (2004).

    CAS  PubMed  Google Scholar 

  60. Liu, B. & Hong, J. S. Role of microglia in inflammation-mediated neurodegenerative diseases: mechanisms and strategies for therapeutic intervention. J. Pharmacol. Exp. Ther. 304, 1–7 (2003).

    CAS  PubMed  Google Scholar 

  61. Miller, J. R. et al. RNA-Seq of Huntington’s disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation. Hum. Mol. Genet. 25, 2893–2904 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Ellrichmann, G., Reick, C., Saft, C. & Linker, R. A. The role of the immune system in Huntington’s disease. Clin. Dev. Immunol. 2013, 1–11 (2013).

    Google Scholar 

  63. Palpagama, T. H., Waldvogel, H. J., Faull, R. L. M. & Kwakowsky, A. The role of microglia and astrocytes in Huntington’s disease. Front. Mol. Neurosci. 12, 258 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Beal, M. F. et al. Neurochemical and histologic characterization of striatal excitotoxic lesions produced by the mitochondrial toxin 3-nitropropionic acid. J. Neurosci. 13, 4181–4192 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Browne, S. E. & Beal, M. F. The energetics of Huntington’s disease. Neurochem. Res. 29, 531–546 (2004).

    CAS  PubMed  Google Scholar 

  66. Mochel, F. et al. Abnormal response to cortical activation in early stages of Huntington disease. Mov. Disord. 27, 907–910 (2012).

    CAS  PubMed  Google Scholar 

  67. Mochel, F. et al. Early alterations of brain cellular energy homeostasis in Huntington disease models. J. Biol. Chem. 287, 1361–1370 (2012).

    CAS  PubMed  Google Scholar 

  68. Goebel, H. H., Heipertz, R., Scholz, W., Iqbal, K. & Tellez-Nagel, I. Juvenile Huntington chorea: clinical, ultrastructural, and biochemical studies. Neurology 28, 23–31 (1978).

    CAS  PubMed  Google Scholar 

  69. Kim, J. et al. Mitochondrial loss, dysfunction and altered dynamics in Huntington’s disease. Hum. Mol. Genet. 19, 3919–3935 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Johri, A., Chandra, A. & Flint Beal, M. PGC-1α, mitochondrial dysfunction, and Huntington’s disease. Free Radic. Biol. Med. 62, 37–46 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Gu, M. et al. Mitochondrial defect in Huntington’s disease caudate nucleus. Ann. Neurol. 39, 385–389 (1996).

    CAS  PubMed  Google Scholar 

  72. Browne, S. E. et al. Oxidative damage and metabolic dysfunction in Huntington’s disease: selective vulnerability of the basal ganglia. Ann. Neurol. 41, 646–653 (1997).

    CAS  PubMed  Google Scholar 

  73. Napoli, E. et al. Defective mitochondrial disulfide relay system, altered mitochondrial morphology and function in Huntington’s disease. Hum. Mol. Genet. 22, 989–1004 (2013).

    CAS  PubMed  Google Scholar 

  74. Naia, L. et al. Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington’s disease human lymphoblasts. Mol. Neurobiol. 51, 331–348 (2015).

    CAS  PubMed  Google Scholar 

  75. Reynolds, N. C. Jr., Prost, R. W. & Mark, L. P. Heterogeneity in 1H-MRS profiles of presymptomatic and early manifest Huntington’s disease. Brain Res. 1031, 82–89 (2005).

    CAS  PubMed  Google Scholar 

  76. Jenkins, B. G., Koroshetz, W. J., Beal, M. F. & Rosen, B. R. Evidence for impairment of energy metabolism in vivo in Huntington’s disease using localized 1H NMR spectroscopy. Neurology 43, 2689–2695 (1993).

    CAS  PubMed  Google Scholar 

  77. Antonini, A. et al. Striatal glucose metabolism and dopamine D2 receptor binding in asymptomatic gene carriers and patients with Huntington’s disease. Brain 119 (Pt 6), 2085–2095 (1996).

    PubMed  Google Scholar 

  78. Feigin, A. et al. Metabolic network abnormalities in early Huntington’s disease: an [(18)F]FDG PET study. J. Nucl. Med. 42, 1591–1595 (2001).

    CAS  PubMed  Google Scholar 

  79. Orr, A. L. et al. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J. Neurosci. 28, 2783–2792 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Trushina, E. et al. Mutant huntingtin impairs axonal trafficking in mammalian neurons in vivo and in vitro. Mol. Cell Biol. 24, 8195–8209 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Shirendeb, U. et al. Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington’s disease: implications for selective neuronal damage. Hum. Mol. Genet. 20, 1438–1455 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Shirendeb, U. P. et al. Mutant huntingtin’s interaction with mitochondrial protein Drp1 impairs mitochondrial biogenesis and causes defective axonal transport and synaptic degeneration in Huntington’s disease. Hum. Mol. Genet. 21, 406–420 (2012).

    CAS  PubMed  Google Scholar 

  83. Cui, L. et al. Transcriptional repression of PGC-1α by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127, 59–69 (2006).

    CAS  PubMed  Google Scholar 

  84. Choo, Y. S., Johnson, G. V., MacDonald, M., Detloff, P. J. & Lesort, M. Mutant huntingtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum. Mol. Genet. 13, 1407–1420 (2004).

    CAS  PubMed  Google Scholar 

  85. Panov, A. V. et al. Early mitochondrial calcium defects in Huntington’s disease are a direct effect of polyglutamines. Nat. Neurosci. 5, 731–736 (2002).

    CAS  PubMed  Google Scholar 

  86. Yano, H. et al. Inhibition of mitochondrial protein import by mutant huntingtin. Nat. Neurosci. 17, 822–831 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Yablonska, S. et al. Mutant huntingtin disrupts mitochondrial proteostasis by interacting with TIM23. Proc. Natl Acad. Sci. USA 116, 16593–16602 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Marti, E. RNA toxicity induced by expanded CAG repeats in Huntington’s disease. Brain Pathol. 26, 779–786 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Li, L. B., Yu, Z., Teng, X. & Bonini, N. M. RNA toxicity is a component of ataxin-3 degeneration in Drosophila. Nature 453, 1107–1111 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Hsu, R. J. et al. Long tract of untranslated CAG repeats is deleterious in transgenic mice. PLoS ONE 6, e16417 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  91. Wang, L. C. et al. Muscleblind participates in RNA toxicity of expanded CAG and CUG repeats in Caenorhabditis elegans. Cell Mol. Life Sci. 68, 1255–1267 (2011).

    CAS  PubMed  Google Scholar 

  92. Banez-Coronel, M. et al. RAN translation in Huntington disease. Neuron 88, 667–677 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Gao, F. B., Richter, J. D. & Cleveland, D. W. Rethinking unconventional translation in neurodegeneration. Cell 171, 994–1000 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Yang, S. et al. Lack of RAN-mediated toxicity in Huntington’s disease knock-in mice. Proc. Natl Acad. Sci. USA 117, 4411–4417 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Kennedy, L. et al. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum. Mol. Genet. 12, 3359–3367 (2003).

    CAS  PubMed  Google Scholar 

  96. Shelbourne, P. F. et al. Triplet repeat mutation length gains correlate with cell-type specific vulnerability in Huntington disease brain. Hum. Mol. Genet. 16, 1133–1142 (2007).

    CAS  PubMed  Google Scholar 

  97. Swami, M. et al. Somatic expansion of the Huntington’s disease CAG repeat in the brain is associated with an earlier age of disease onset. Hum. Mol. Genet. 18, 3039–3047 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Genetic Modifiers of Huntington’s Disease (GeM-HD) consortium. CAG repeat not polyglutamine length determines timing of Huntington’s disease onset. Cell 178, 887–900.e14 (2019).

    Google Scholar 

  99. Telenius, H. et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum. Mol. Genet. 2, 1535–1540 (1993).

    CAS  PubMed  Google Scholar 

  100. Aronin, N. et al. CAG expansion affects the expression of mutant huntingtin in the Huntington’s disease brain. Neuron 15, 1193–1201 (1995).

    CAS  PubMed  Google Scholar 

  101. Ansved, T., Lundin, A. & Anvret, M. Larger CAG expansions in skeletal muscle compared with lymphocytes in Kennedy disease but not in Huntington disease. Neurology 51, 1442–1444 (1998).

    CAS  PubMed  Google Scholar 

  102. Squitieri, F., Ciarmiello, A., Di Donato, S. & Frati, L. The search for cerebral biomarkers of Huntington’s disease: a review of genetic models of age at onset prediction. Eur. J. Neurol. 13, 408–415 (2006).

    CAS  PubMed  Google Scholar 

  103. Kaplan, S., Itzkovitz, S. & Shapiro, E. A universal mechanism ties genotype to phenotype in trinucleotide diseases. PLoS Comput. Biol. 3, e235 (2007).

    PubMed  PubMed Central  Google Scholar 

  104. La Spada, A. R. Trinucleotide repeat instability: genetic features and molecular mechanisms. Brain Pathol. 7, 943–963 (1997).

    PubMed  Google Scholar 

  105. Wright, G. E. B. et al. Length of uninterrupted CAG repeats, independent of polyglutamine size, results in increased somatic instability and hastened age of onset in Huntington disease. Am. J. Hum. Genet.104, 1116–1126 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Gusella, J. F., MacDonald, M. E. & Lee, J. M. Genetic modifiers of Huntington’s disease. Mov. Disord. 29, 1359–1365 (2014).

    CAS  PubMed  Google Scholar 

  107. Wexler, N. S. et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl Acad. Sci. USA 101, 3498–3503 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. Genetic Modifiers of Huntington’s Disease (GeM-HD) consortium. Identification of genetic factors that modify clinical onset of Huntington’s disease. Cell 162, 516–526 (2015).

    Google Scholar 

  109. Porro, A. et al. FAN1 interaction with ubiquitylated PCNA alleviates replication stress and preserves genomic integrity independently of BRCA2. Nat. Commun. 8, 1073 (2017).

    PubMed  PubMed Central  Google Scholar 

  110. Goold, R. et al. FAN1 modifies Huntington’s disease progression by stabilising the expanded HTT CAG repeat. Hum. Mol. Genet. 28, 650–661 (2018).

    PubMed Central  Google Scholar 

  111. Zhao, X. N. & Usdin, K. FAN1 protects against repeat expansions in a fragile X mouse model. DNA Repair 69, 1–5 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Ortega, Z. & Lucas, J. J. Ubiquitin-proteasome system involvement in Huntington’s disease. Front. Mol. Neurosci. 7, 77 (2014).

    PubMed  PubMed Central  Google Scholar 

  113. Koyuncu, S. et al. The ubiquitin ligase UBR5 suppresses proteostasis collapse in pluripotent stem cells from Huntington’s disease patients. Nat. Commun. 9, 2886 (2018).

    PubMed  PubMed Central  Google Scholar 

  114. Pinto, R. M. et al. Mismatch repair genes Mlh1 and Mlh3 modify CAG instability in Huntington’s disease mice: genome-wide and candidate approaches. PLoS Genet. 9, e1003930 (2013).

    PubMed  PubMed Central  Google Scholar 

  115. Hensman Moss, D. J. H. et al. Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study. Lancet. Neurol. 16, 701–711 (2017).

    Google Scholar 

  116. Iyer, R. R., Pluciennik, A., Napierala, M. & Wells, R. D. DNA triplet repeat expansion and mismatch repair. Annu. Rev. Biochem. 84, 199–226 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Dragileva, E. et al. Intergenerational and striatal CAG repeat instability in Huntington’s disease knock-in mice involve different DNA repair genes. Neurobiol. Dis. 33, 37–47 (2009).

    CAS  PubMed  Google Scholar 

  118. Tome, S. et al. MSH3 polymorphisms and protein levels affect CAG repeat instability in Huntington’s disease mice. PLoS Genet. 9, e1003280 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Anderson, D. D., Quintero, C. M. & Stover, P. J. Identification of a de novo thymidylate biosynthesis pathway in mammalian mitochondria. Proc. Natl Acad. Sci. USA 108, 15163–15168 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Flower, M. et al. MSH3 modifies somatic instability and disease severity in Huntington’s and myotonic dystrophy type 1. Brain 142, 1876–1886 (2019).

    PubMed Central  Google Scholar 

  121. Andresen, J. M. et al. Replication of twelve association studies for Huntington’s disease residual age of onset in large Venezuelan kindreds. J. Med. Genet. 44, 44–50 (2007).

    CAS  PubMed  Google Scholar 

  122. Holbert, S. et al. The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc. Natl Acad. Sci. USA 98, 1811–1816 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Kozlov, S. V. et al. Reactive oxygen species (ROS)-activated ATM-dependent phosphorylation of cytoplasmic substrates identified by large-scale phosphoproteomics screen. Mol. Cell. Proteomics 15, 1032–1047 (2016).

    CAS  PubMed  Google Scholar 

  124. Massey, T. H. & Jones, L. The central role of DNA damage and repair in CAG repeat diseases. Dis. Model. Mech. 11, dmm031930 (2018).

    PubMed  PubMed Central  Google Scholar 

  125. Howes, T. R. & Tomkinson, A. E. DNA ligase I, the replicative DNA ligase. Subcell. Biochem. 62, 327–341 (2012).

    CAS  PubMed  Google Scholar 

  126. Lopez Castel, A., Tomkinson, A. E. & Pearson, C. E. CTG/CAG repeat instability is modulated by the levels of human DNA ligase I and its interaction with proliferating cell nuclear antigen: a distinction between replication and slipped-DNA repair. J. Biol. Chem. 284, 26631–26645 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Tome, S. et al. Maternal germline-specific effect of DNA ligase I on CTG/CAG instability. Hum. Mol. Genet. 20, 2131–2143 (2011).

    CAS  PubMed  Google Scholar 

  128. Gomes-Pereira, M., Fortune, M. T., Ingram, L., McAbney, J. P. & Monckton, D. G. Pms2 is a genetic enhancer of trinucleotide CAG.CTG repeat somatic mosaicism: implications for the mechanism of triplet repeat expansion. Hum. Mol. Genet. 13, 1815–1825 (2004).

    CAS  PubMed  Google Scholar 

  129. Bettencourt, C. et al. DNA repair pathways underlie a common genetic mechanism modulating onset in polyglutamine diseases. Ann. Neurol. 79, 983–990 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Morales, F. et al. A polymorphism in the MSH3 mismatch repair gene is associated with the levels of somatic instability of the expanded CTG repeat in the blood DNA of myotonic dystrophy type 1 patients. DNA Repair 40, 57–66 (2016).

    CAS  PubMed  Google Scholar 

  131. Nakatani, R., Nakamori, M., Fujimura, H., Mochizuki, H. & Takahashi, M. P. Large expansion of CTG•CAG repeats is exacerbated by MutSβ in human cells. Sci. Rep. 5, 11020 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Halabi, A., Fuselier, K. T. B. & Grabczyk, E. GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one. Nucleic Acids Res. 46, 4022–4032 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Panigrahi, G. B., Slean, M. M., Simard, J. P. & Pearson, C. E. Human mismatch repair protein hMutL is required to repair short slipped-DNAs of trinucleotide repeats. J. Biol. Chem. 287, 41844–41850 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Lin, Y., Dion, V. & Wilson, J. H. Transcription promotes contraction of CAG repeat tracts in human cells. Nat. Struct. Mol. Biol. 13, 179–180 (2006).

    CAS  PubMed  Google Scholar 

  135. Lin, Y. & Wilson, J. H. Diverse effects of individual mismatch repair components on transcription-induced CAG repeat instability in human cells. DNA Repair 8, 878–885 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Gannon, A. M., Frizzell, A., Healy, E. & Lahue, R. S. MutSbeta and histone deacetylase complexes promote expansions of trinucleotide repeats in human cells. Nucleic Acids Res. 40, 10324–10333 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Keogh, N., Chan, K. Y., Li, G. M. & Lahue, R. S. MutSβ abundance and Msh3 ATP hydrolysis activity are important drivers of CTG*CAG repeat expansions. Nucleic Acids Res. 45, 10068–10078 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Seriola, A. et al. Huntington’s and myotonic dystrophy hESCs: down-regulated trinucleotide repeat instability and mismatch repair machinery expression upon differentiation. Hum. Mol. Genet. 20, 176–185 (2011).

    CAS  PubMed  Google Scholar 

  139. Du, J., Campau, E., Soragni, E., Jespersen, C. & Gottesfeld, J. M. Length-dependent CTG.CAG triplet-repeat expansion in myotonic dystrophy patient-derived induced pluripotent stem cells. Hum. Mol. Genet. 22, 5276–5287 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Axford, M. M. et al. Detection of slipped-DNAs at the trinucleotide repeats of the myotonic dystrophy type I disease locus in patient tissues. PLoS Genet. 9, e1003866 (2013).

    PubMed  PubMed Central  Google Scholar 

  141. Schmidt, M. H. & Pearson, C. E. Disease-associated repeat instability and mismatch repair. DNA Repair 38, 117–126 (2016).

    CAS  PubMed  Google Scholar 

  142. Carethers, J. M. Microsatellite instability pathway and EMAST in colorectal cancer. Curr. Colorectal Cancer Rep. 13, 73–80 (2017).

    PubMed  PubMed Central  Google Scholar 

  143. Gacy, A. M., Goellner, G., Juranic, N., Macura, S. & McMurray, C. T. Trinucleotide repeats that expand in human disease form hairpin structures in vitro. Cell 81, 533–540 (1995).

    CAS  PubMed  Google Scholar 

  144. Gonitel, R. et al. DNA instability in postmitotic neurons. Proc. Natl Acad. Sci. USA 105, 3467–3472 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Gomes-Pereira, M. et al. Disease-associated CAG·CTG triplet repeats expand rapidly in non-dividing mouse cells, but cell cycle arrest is insufficient to drive expansion. Nucleic Acids Res. 42, 7047–7056 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Slean, M. M. et al. Absence of MutSβ leads to the formation of slipped-DNA for CTG/CAG contractions at primate replication forks. DNA Repair 42, 107–118 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Liu, G., Chen, X., Bissler, J. J., Sinden, R. R. & Leffak, M. Replication-dependent instability at (CTG)•(CAG) repeat hairpins in human cells. Nat. Chem. Biol. 6, 652–659 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Muro, Y., Sugiura, K., Mimori, T. & Akiyama, M. DNA mismatch repair enzymes: genetic defects and autoimmunity. Clinica Chim. Acta. 442, 102–109 (2015).

    CAS  Google Scholar 

  149. Sehgal, R. et al. Lynch syndrome: an updated review. Genes 5, 497–507 (2014).

    PubMed  PubMed Central  Google Scholar 

  150. Buniello, A. et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res. 47, D1005–D1012 (2019).

    CAS  PubMed  Google Scholar 

  151. Ochaba, J. et al. PIAS1 regulates mutant huntingtin accumulation and Huntington’s disease-associated phenotypes in vivo. Neuron 90, 507–520 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72, 971–983 (1993).

    Google Scholar 

  153. Lin, B. et al. Differential 3′ polyadenylation of the Huntington disease gene results in two mRNA species with variable tissue expression. Hum. Mol. Genet. 2, 1541–1545 (1993).

    CAS  PubMed  Google Scholar 

  154. Landles, C. et al. Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in huntington disease. J. Biol. Chem. 285, 8808–8823 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  155. Neueder, A. et al. The pathogenic exon 1 HTT protein is produced by incomplete splicing in Huntington’s disease patients. Sci. Rep. 7, 1307–1307 (2017).

    PubMed  PubMed Central  Google Scholar 

  156. Bates, G., Tabrizi, S. & Jones, L. Huntington’s Disease (Oxford University Press, 2014).

  157. Beck, M. & Hurt, E. The nuclear pore complex: understanding its function through structural insight. Nat. Rev. Mol. Cell Biol. 18, 73–89 (2017).

    CAS  PubMed  Google Scholar 

  158. Basel-Vanagaite, L. et al. Mutated nup62 causes autosomal recessive infantile bilateral striatal necrosis. Ann. Neurol. 60, 214–222 (2006).

    CAS  PubMed  Google Scholar 

  159. Cavazza, T. & Vernos, I. The RanGTP pathway: from nucleo-cytoplasmic transport to spindle assembly and beyond. Front. Cell Dev. Biol. 3, 82 (2015).

    PubMed  Google Scholar 

  160. Hetzer, M., Gruss, O. J. & Mattaj, I. W. The Ran GTPase as a marker of chromosome position in spindle formation and nuclear envelope assembly. Nat. Cell Biol. 4, E177–E184 (2002).

    CAS  PubMed  Google Scholar 

  161. Hosp, F. et al. Quantitative interaction proteomics of neurodegenerative disease proteins. Cell Rep. 11, 1134–1146 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Grima, J. C. et al. Mutant huntingtin disrupts the nuclear pore complex. Neuron 94, 93–107.e6 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhang, Y. J. et al. C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins. Nat. Neurosci. 19, 668–677 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Shi, K. Y. et al. Toxic PRn poly-dipeptides encoded by the C9orf72 repeat expansion block nuclear import and export. Proc. Natl Acad. Sci. USA 114, E1111–E1117 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. Ruba, A. & Yang, W. O-GlcNAc-ylation in the nuclear pore complex. Cell Mol. Bioeng. 9, 227–233 (2016).

    CAS  PubMed  Google Scholar 

  166. Haines, J. D. et al. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat. Neurosci. 18, 511–520 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Archbold, H. C. et al. TDP43 nuclear export and neurodegeneration in models of amyotrophic lateral sclerosis and frontotemporal dementia. Sci. Rep. 8, 4606 (2018).

    PubMed  PubMed Central  Google Scholar 

  169. Guo, Q. et al. The cryo-electron microscopy structure of huntingtin. Nature 555, 117–120 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Peters, M. F. & Ross, C. A. Isolation of a 40-kDa huntingtin-associated protein. J. Biol. Chem. 276, 3188–3194 (2001).

    CAS  PubMed  Google Scholar 

  171. Pal, A., Severin, F., Lommer, B., Shevchenko, A. & Zerial, M. Huntingtin-HAP40 complex is a novel Rab5 effector that regulates early endosome motility and is up-regulated in Huntington’s disease. J. Cell Biol. 172, 605–618 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Li, W., Serpell, L. C., Carter, W. J., Rubinsztein, D. C. & Huntington, J. A. Expression and characterization of full-length human huntingtin, an elongated HEAT repeat protein. J. Biol. Chem. 281, 15916–15922 (2006).

    CAS  PubMed  Google Scholar 

  173. Andrade, M. A. & Bork, P. HEAT repeats in the Huntington’s disease protein. Nat. Genet. 11, 115–116 (1995).

    CAS  PubMed  Google Scholar 

  174. Seong, I. S. et al. Huntingtin facilitates polycomb repressive complex 2. Hum. Mol. Genet. 19, 573–583 (2010).

    CAS  PubMed  Google Scholar 

  175. Ratovitski, T. et al. Post-translational modifications (PTMs), identified on endogenous huntingtin, cluster within proteolytic domains between HEAT repeats. J. Proteome Res. 16, 2692–2708 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Arbez, N. et al. Post-translational modifications clustering within proteolytic domains decrease mutant huntingtin toxicity. J. Biol. Chem. 292, 19238–19249 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Yee, L. M., Lively, T. G. & McShane, L. M. Biomarkers in early-phase trials: fundamental issues. Bioanalysis 10, 933–944 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  178. Rodrigues, F. B., Byrne, L. M. & Wild, E. J. Biofluid biomarkers in Huntington’s disease. Methods Mol. Biol. 1780, 329–396 (2018).

    CAS  PubMed  Google Scholar 

  179. Silajdzic, E. & Bjorkqvist, M. A critical evaluation of wet biomarkers for Huntington’s disease: current status and ways forward. J. Huntington’s Dis. 7, 109–135 (2018).

    Google Scholar 

  180. Southwell, A. L. et al. Ultrasensitive measurement of huntingtin protein in cerebrospinal fluid demonstrates increase with Huntington disease stage and decrease following brain huntingtin suppression. Sci. Rep. 5, 12166 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Wild, E. J. et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington’s disease patients. J. Clin. Invest. 125, 1979–1986 (2015).

    PubMed  PubMed Central  Google Scholar 

  182. Fodale, V. et al. Validation of ultrasensitive mutant huntingtin detection in human cerebrospinal fluid by single molecule counting immunoassay. J. Huntington’s Dis. 6, 349–361 (2017).

    CAS  Google Scholar 

  183. Byrne, L. M. et al. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease. Sci. Transl Med. 10, eaat7108 (2018).

    PubMed  Google Scholar 

  184. Tabrizi, S. J. et al. Targeting huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 380, 2307–2316 (2019).

    CAS  PubMed  Google Scholar 

  185. Shahim, P., Zetterberg, H., Tegner, Y. & Blennow, K. Serum neurofilament light as a biomarker for mild traumatic brain injury in contact sports. Neurology 88, 1788–1794 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Constantinescu, R., Romer, M., Oakes, D., Rosengren, L. & Kieburtz, K. Levels of the light subunit of neurofilament triplet protein in cerebrospinal fluid in Huntington’s disease. Parkinsonism Relat. Disord. 15, 245–248 (2009).

    PubMed  Google Scholar 

  187. Vinther-Jensen, T. et al. Selected CSF biomarkers indicate no evidence of early neuroinflammation in Huntington disease. Neurol. Neuroimmunol. Neuroinflamm. 3, e287 (2016).

    PubMed  PubMed Central  Google Scholar 

  188. Niemelä, V., Landtblom, A.-M., Blennow, K. & Sundblom, J. Tau or neurofilament light — which is the more suitable biomarker for Huntington’s disease? PLoS ONE 12, e0172762 (2017).

    PubMed  PubMed Central  Google Scholar 

  189. Byrne, L. M. et al. Neurofilament light protein in blood as a potential biomarker of neurodegeneration in Huntington’s disease: a retrospective cohort analysis. Lancet. Neurol. 16, 601–609 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Rodrigues, F. B. et al. Cerebrospinal fluid inflammatory biomarkers reflect clinical severity in Huntington’s disease. PLoS ONE 11, e0163479 (2016).

    PubMed  PubMed Central  Google Scholar 

  191. Soylu-Kucharz, R. et al. Neurofilament light protein in CSF and blood is associated with neurodegeneration and disease severity in Huntington’s disease R6/2 mice. Sci. Rep. 7, 14114 (2017).

    PubMed  PubMed Central  Google Scholar 

  192. Johnson, E. B. et al. Neurofilament light protein in blood predicts regional atrophy in Huntington disease. Neurology 90, e717–e723 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Vinther-Jensen, T., Budtz-Jorgensen, E., Simonsen, A. H., Nielsen, J. E. & Hjermind, L. E. YKL-40 in cerebrospinal fluid in Huntington’s disease–a role in pathology or a nonspecific response to inflammation? Parkinsonism Relat. Disord. 20, 1301–1303 (2014).

    PubMed  Google Scholar 

  194. Rodrigues, F. B. et al. Cerebrospinal fluid total tau concentration predicts clinical phenotype in Huntington’s disease. J. Neurochem. 139, 22–25 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Davis, M. Y., Keene, C. D., Jayadev, S. & Bird, T. The co-occurrence of Alzheimer’s disease and Huntington’s disease: a neuropathological study of 15 elderly Huntington’s disease subjects. J. Huntington’s Dis. 3, 209–217 (2014).

    CAS  Google Scholar 

  196. Jellinger, K. A. Alzheimer-type lesions in Huntington’s disease. J. Neural Transm. 105, 787–799 (1998).

    CAS  PubMed  Google Scholar 

  197. Vuono, R. et al. The role of tau in the pathological process and clinical expression of Huntington’s disease. Brain 138, 1907–1918 (2015).

    PubMed  PubMed Central  Google Scholar 

  198. St-Amour, I., Turgeon, A., Goupil, C., Planel, E. & Hebert, S. S. Co-occurrence of mixed proteinopathies in late-stage Huntington’s disease. Acta Neuropathol. 135, 249–265 (2018).

    CAS  PubMed  Google Scholar 

  199. Fernandez-Nogales, M. et al. Huntington’s disease is a four-repeat tauopathy with tau nuclear rods. Nat. Med. 20, 881–885 (2014).

    CAS  PubMed  Google Scholar 

  200. Blum, D. et al. Mutant huntingtin alters tau phosphorylation and subcellular distribution. Hum. Mol. Genet. 24, 76–85 (2015).

    CAS  PubMed  Google Scholar 

  201. Baskota, S. U., Lopez, O. L., Greenamyre, J. T. & Kofler, J. Spectrum of tau pathologies in Huntington’s disease. Lab. Invest. 99, 1068–1077 (2019).

    CAS  PubMed  Google Scholar 

  202. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03225846 (2020).

  203. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03225833 (2020).

  204. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03761849 (2020).

  205. McColgan, P. & Tabrizi, S. J. Huntington’s disease: a clinical review. Eur. J. Neurol. 25, 24–34 (2018).

    CAS  PubMed  Google Scholar 

  206. Estévez-Fraga, C., Avilés Olmos, I., Mañanes Barral, V. & López-Sendón Moreno, J. L. Therapeutic advances in Huntington’s disease. Expert Opin. Orphan Drugs 4, 809–821 (2016).

    Google Scholar 

  207. Reilmann, R. et al. Safety and efficacy of pridopidine in patients with Huntington’s disease (PRIDE-HD): a phase 2, randomised, placebo-controlled, multicentre, dose-ranging study. Lancet Neurol. 18, 165–176 (2019).

    CAS  PubMed  Google Scholar 

  208. US National Library of Medicine. Randomized, placebo controlled study of the efficacy and safety of PF-02545920 in subjects with Huntington’s disease. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/results/NCT02197130 (2017).

  209. Delnomdedieu, M. PDE10i and HD: learnings from the Amaryllis studies Presented at The CHDI 13th Annual HD Therapeutics Conference. https://chdifoundation.org/2018-conference (2018).

  210. Wild, E. C. J. Pfizer Amaryllis trial ends in disappointment: no improvement in Huntington’s disease symptoms https://en.hdbuzz.net/229 (2016).

  211. McGarry, A. et al. A randomized, double-blind, placebo-controlled trial of coenzyme Q10 in Huntington disease. Neurology 88, 152–159 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 57, 397–404 (2001).

    Google Scholar 

  213. Hersch, S. M. et al. The CREST-E study of creatine for Huntington disease: a randomized controlled trial. Neurology 89, 594–601 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Verny, C. et al. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington’s disease. Mov. Disord. 32, 932–936 (2017).

    CAS  PubMed  Google Scholar 

  215. Reilmann, R. et al. Safety and tolerability of selisistat for the treatment of Huntington’s disease: results from a randomized, double-blind, placebo-controlled phase II trial [abstract]. Neurology 82, S47.004 (2014).

    Google Scholar 

  216. Süssmuth, S. D. et al. An exploratory double-blind, randomized clinical trial with selisistat, a SirT1 inhibitor, in patients with Huntington’s disease. Br. J. Clin. Pharmacol. 79, 465–476 (2015).

    PubMed  PubMed Central  Google Scholar 

  217. Huntington Study Group Reach2HD Investigators. Safety, tolerability, and efficacy of PBT2 in Huntington’s disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 14, 39–47 (2015).

    Google Scholar 

  218. Lopez-Sendon Moreno, J. L. et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with sativex in Huntington’s disease. J. Neurol. 263, 1390–1400 (2016).

    CAS  PubMed  Google Scholar 

  219. Active Biotech. Active Biotech provides update on laquinimod in Huntington’s disease. http://hugin.info/1002/R/2208124/858841.pdf (2018).

  220. Cicchetti, F. et al. Neural transplants in patients with Huntington’s disease undergo disease-like neuronal degeneration. Proc. Natl Acad. Sci. USA 106, 12483–12488 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Freeman, T. B. et al. Transplanted fetal striatum in Huntington’s disease: phenotypic development and lack of pathology. Proc. Natl Acad. Sci. USA 97, 13877–13882 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  222. Bachoud-Levi, A. C. From open to large-scale randomized cell transplantation trials in Huntington’s disease: lessons from the multicentric intracerebral grafting in Huntington’s disease trial (MIG-HD) and previous pilot studies. Prog. Brain Res. 230, 227–261 (2017).

    PubMed  Google Scholar 

  223. Wild, E. J. & Tabrizi, S. J. Therapies targeting DNA and RNA in Huntington’s disease. Lancet Neurol. 16, 837–847 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Tabrizi, S. J., Ghosh, R. & Leavitt, B. R. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron 102, 899 (2019).

    CAS  PubMed  Google Scholar 

  225. Lee, J. M. et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology 78, 690–695 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  226. Kordasiewicz, H. B. et al. Sustained therapeutic reversal of Huntington’s disease by transient repression of huntingtin synthesis. Neuron 74, 1031–1044 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  227. Lu, X.-H. & Yang, X. W. “Huntingtin holiday”: progress toward an antisense therapy for Huntington’s disease. Neuron 74, 964–966 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  228. Stanek, L. M. et al. Antisense oligonucleotide-mediated correction of transcriptional dysregulation is correlated with behavioral benefits in the YAC128 mouse model of Huntington’s disease. J. Huntington’s Dis. 2, 217–228 (2013).

    CAS  Google Scholar 

  229. Miniarikova, J. et al. AAV5-miHTT gene therapy demonstrates suppression of mutant huntingtin aggregation and neuronal dysfunction in a rat model of Huntington’s disease. Gene Ther. 24, 630–639 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Gauthier, L. R. et al. Huntingtin controls neurotrophic support and survival of neurons by enhancing BDNF vesicular transport along microtubules. Cell 118, 127–138 (2004).

    CAS  PubMed  Google Scholar 

  231. Duyao, M. P. et al. Inactivation of the mouse Huntington’s disease gene homolog Hdh. Science 269, 407–410 (1995).

    CAS  PubMed  Google Scholar 

  232. Dragatsis, I., Levine, M. S. & Zeitlin, S. Inactivation of Hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nat. Genet. 26, 300–306 (2000).

    CAS  PubMed  Google Scholar 

  233. Colin, E. et al. Huntingtin phosphorylation acts as a molecular switch for anterograde/retrograde transport in neurons. EMBO J. 27, 2124–2134 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  234. Strehlow, A. N., Li, J. Z. & Myers, R. M. Wild-type huntingtin participates in protein trafficking between the Golgi and the extracellular space. Hum. Mol. Genet. 16, 391–409 (2007).

    CAS  PubMed  Google Scholar 

  235. Velier, J. et al. Wild-type and mutant huntingtins function in vesicle trafficking in the secretory and endocytic pathways. Exp. Neurol. 152, 34–40 (1998).

    CAS  PubMed  Google Scholar 

  236. Brandstaetter, H., Kruppa, A. J. & Buss, F. Huntingtin is required for ER-to-Golgi transport and for secretory vesicle fusion at the plasma membrane. Dis. Model. Mech. 7, 1335–1340 (2014).

    PubMed  PubMed Central  Google Scholar 

  237. Caviston, J. P. & Holzbaur, E. L. Huntingtin as an essential integrator of intracellular vesicular trafficking. Trends Cell Biol. 19, 147–155 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  238. Kegel, K. B. et al. Huntingtin is present in the nucleus, interacts with the transcriptional corepressor C-terminal binding protein, and represses transcription. J. Biol. Chem. 277, 7466–7476 (2002).

    CAS  PubMed  Google Scholar 

  239. Zuccato, C. et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes. Nat. Genet. 35, 76–83 (2003).

    CAS  PubMed  Google Scholar 

  240. McFarland, K. N. et al. MeCP2: a novel huntingtin interactor. Hum. Mol. Genet. 23, 1036–1044 (2014).

    CAS  PubMed  Google Scholar 

  241. DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14, 1075–1081 (1995).

    CAS  PubMed  Google Scholar 

  242. Marcora, E. & Kennedy, M. B. The Huntington’s disease mutation impairs huntingtin’s role in the transport of NF-κB from the synapse to the nucleus. Hum. Mol. Genet. 19, 4373–4384 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  243. McKinstry, S. U. et al. Huntingtin is required for normal excitatory synapse development in cortical and striatal circuits. J. Neurosci. 34, 9455–9472 (2014).

    PubMed  PubMed Central  Google Scholar 

  244. Hoffner, G., Kahlem, P. & Djian, P. Perinuclear localization of huntingtin as a consequence of its binding to microtubules through an interaction with beta-tubulin: relevance to Huntington’s disease. J. Cell Sci. 115, 941–948 (2002).

    CAS  PubMed  Google Scholar 

  245. Caviston, J. P., Ross, J. L., Antony, S. M., Tokito, M. & Holzbaur, E. L. Huntingtin facilitates dynein/dynactin-mediated vesicle transport. Proc. Natl Acad. Sci. USA 104, 10045–10050 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Anne, S. L., Saudou, F. & Humbert, S. Phosphorylation of huntingtin by cyclin-dependent kinase 5 is induced by DNA damage and regulates wild-type and mutant huntingtin toxicity in neurons. J. Neurosci. 27, 7318–7328 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  247. Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820–5825 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Franich, N. R. et al. AAV vector-mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington’s disease. Mol. Ther. 16, 947–956 (2008).

    CAS  PubMed  Google Scholar 

  249. McBride, J. L. et al. Preclinical safety of RNAi-mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol. Ther. 19, 2152–2162 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. Grondin, R. et al. Six-month partial suppression of huntingtin is well tolerated in the adult rhesus striatum. Brain 135, 1197–1209 (2012).

    PubMed  PubMed Central  Google Scholar 

  251. Wang, G., Liu, X., Gaertig, M. A., Li, S. & Li, X. J. Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis. Proc. Natl Acad. Sci. USA 113, 3359–3364 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  252. Ambrose, C. M. et al. Structure and expression of the Huntington’s disease gene: evidence against simple inactivation due to an expanded CAG repeat. Somat. Cell Mol. Genet. 20, 27–38 (1994).

    CAS  PubMed  Google Scholar 

  253. Gagnon, K. T. et al. Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 49, 10166–10178 (2010).

    CAS  PubMed  Google Scholar 

  254. Yu, D. et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895–908 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  255. Garriga-Canut, M. et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc. Natl Acad. Sci. USA 109, E3136–E3145 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  256. van Bilsen, P. H. et al. Identification and allele-specific silencing of the mutant huntingtin allele in Huntington’s disease patient-derived fibroblasts. Hum. Gene Ther. 19, 710–719 (2008).

    PubMed  Google Scholar 

  257. Monteys, A. M., Ebanks, S. A., Keiser, M. S. & Davidson, B. L. CRISPR/Cas9 editing of the mutant huntingtin allele in vitro and in vivo. Mol. Ther. 25, 12–23 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Shin, J. W. et al. Permanent inactivation of Huntington’s disease mutation by personalized allele-specific CRISPR/Cas9. Hum. Mol. Genet. 25, 4566–4576 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Lindow, M. et al. Assessing unintended hybridization-induced biological effects of oligonucleotides. Nat. Biotechnol. 30, 920–923 (2012).

    CAS  PubMed  Google Scholar 

  260. Kay, C. et al. Huntingtin haplotypes provide prioritized target panels for allele-specific silencing in Huntington disease patients of European ancestry. Mol. Ther. 23, 1759–1771 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Lombardi, M. S. et al. A majority of Huntington’s disease patients may be treatable by individualized allele-specific RNA interference. Exp. Neurol. 217, 312–319 (2009).

    CAS  PubMed  Google Scholar 

  262. Pfister, E. L. et al. Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington’s disease patients. Curr. Biol. 19, 774–778 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. Setten, R. L., Rossi, J. J. & Han, S. P. The current state and future directions of RNAi-based therapeutics. Nat. Rev. Drug. Discov. 18, 421–446 (2019).

    CAS  PubMed  Google Scholar 

  264. Ha, M. & Kim, V. N. Regulation of microRNA biogenesis. Nat. Rev. Mol. Cell Biol. 15, 509–524 (2014).

    CAS  PubMed  Google Scholar 

  265. Ahmadzada, T., Reid, G. & McKenzie, D. R. Fundamentals of siRNA and miRNA therapeutics and a review of targeted nanoparticle delivery systems in breast cancer. Biophys. Rev. 10, 69–86 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Rodriguez-Lebron, E., Denovan-Wright, E. M., Nash, K., Lewin, A. S. & Mandel, R. J. Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington’s disease transgenic mice. Mol. Ther. 12, 618–633 (2005).

    CAS  PubMed  Google Scholar 

  267. Wang, Y. L. et al. Clinico-pathological rescue of a model mouse of Huntington’s disease by siRNA. Neurosci. Res. 53, 241–249 (2005).

    CAS  PubMed  Google Scholar 

  268. DiFiglia, M. et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc. Natl Acad. Sci. USA 104, 17204–17209 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  269. Machida, Y. et al. rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse. Biochem. Biophys. Res. Commun. 343, 190–197 (2006).

    CAS  PubMed  Google Scholar 

  270. Boudreau, R. L. et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol. Ther. 17, 1053–1063 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  271. McBride, J. L. et al. Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proc. Natl Acad. Sci. USA 105, 5868–5873 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Drouet, V. et al. Sustained effects of nonallele-specific huntingtin silencing. Ann. Neurol. 65, 276–285 (2009).

    CAS  PubMed  Google Scholar 

  273. Stanek, L. M. et al. Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington’s disease. Hum. Gene Ther. 25, 461–474 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. de Fougerolles, A. R. Delivery vehicles for small interfering RNA in vivo. Hum. Gene Ther. 19, 125–132 (2008).

    PubMed  Google Scholar 

  275. Wang, D., Tai, P. W. L. & Gao, G. Adeno-associated virus vector as a platform for gene therapy delivery. Nat. Rev. Drug Discov. 18, 358–378 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  276. Lykken, E. A., Shyng, C., Edwards, R. J., Rozenberg, A. & Gray, S. J. Recent progress and considerations for AAV gene therapies targeting the central nervous system. J. Neurodev. Disord. 10, 16 (2018).

    PubMed  PubMed Central  Google Scholar 

  277. Dufour, B. D., Smith, C. A., Clark, R. L., Walker, T. R. & McBride, J. L. Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in Huntington’s disease mice. Mol. Ther. 22, 797–810 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  278. Deverman, B. E. et al. Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain. Nat. Biotechnol. 34, 204–209 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  279. Matsuzaki, Y. et al. Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci. Lett. 665, 182–188 (2018).

    CAS  PubMed  Google Scholar 

  280. Jackson, A. L. & Linsley, P. S. Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nat. Rev. Drug. Discov. 9, 57–67 (2010).

    CAS  PubMed  Google Scholar 

  281. Grimm, D. et al. Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537–541 (2006).

    CAS  PubMed  Google Scholar 

  282. Borel, F. et al. In vivo knock-down of multidrug resistance transporters ABCC1 and ABCC2 by AAV-delivered shRNAs and by artificial miRNAs. J. RNAi Gene Silencing 7, 434–442 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Meng, Z. & Lu, M. RNA interference-induced innate immunity, off-target effect, or immune adjuvant? Front. Immunol. 8, 331 (2017).

    PubMed  PubMed Central  Google Scholar 

  284. Louis Jeune, V., Joergensen, J. A., Hajjar, R. J. & Weber, T. Pre-existing anti-adeno-associated virus antibodies as a challenge in AAV gene therapy. Hum. Gene Ther. Methods 24, 59–67 (2013).

    CAS  PubMed  Google Scholar 

  285. Rafii, M. S. et al. Adeno-associated viral vector (serotype 2)-nerve growth factor for patients with Alzheimer disease: a randomized clinical trial. JAMA Neurol. 75, 834–841 (2018).

    PubMed  PubMed Central  Google Scholar 

  286. Kristen, A. V. et al. Patisiran, an RNAi therapeutic for the treatment of hereditary transthyretin-mediated amyloidosis. Neurodegener. Dis. Manag. 9, 5–23 (2019).

    PubMed  Google Scholar 

  287. Adams, D. et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N. Engl. J. Med. 379, 11–21 (2018).

    CAS  PubMed  Google Scholar 

  288. Shankar, R., Joshi, M. & Pathak, K. Lipid nanoparticles: a novel approach for brain targeting. Pharm. Nanotechnol. 6, 81–93 (2018).

    CAS  PubMed  Google Scholar 

  289. Cullis, P. R. & Hope, M. J. Lipid nanoparticle systems for enabling gene therapies. Mol. Ther. 25, 1467–1475 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  290. Neves, A. R., Queiroz, J. F. & Reis, S. Brain-targeted delivery of resveratrol using solid lipid nanoparticles functionalized with apolipoprotein E. J. Nanobiotechnol. 14, 27 (2016).

    Google Scholar 

  291. Salvalaio, M. et al. Targeted polymeric nanoparticles for brain delivery of high molecular weight molecules in lysosomal storage disorders. PLoS ONE 11, e0156452 (2016).

    PubMed  PubMed Central  Google Scholar 

  292. uniQure. uniQure announces FDA clearance of investigational new drug application for AMT-130 in Huntington’s disease. https://www.globenewswire.com/news-release/2019/01/22/1703263/0/en/uniQure-Announces-FDA-Clearance-of-Investigational-New-Drug-Application-for-AMT-130-in-Huntington-s-Disease.html (2019).

  293. Evers, M. M. et al. AAV5-miHTT gene therapy demonstrates broad distribution and strong human mutant huntingtin lowering in a Huntington’s disease minipig model. Mol. Ther. 26, 2163–2177 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  294. Hadaczek, P. et al. Widespread AAV1- and AAV2-mediated transgene expression in the nonhuman primate brain: implications for Huntington’s disease. Mol. Ther. Methods Clin. Dev. 3, 16037 (2016).

    PubMed  PubMed Central  Google Scholar 

  295. Voyager Therapeutics. Voyager Therapeutics announces preclinical data for Huntington’s disease and amyotrophic lateral sclerosis programs at the Congress of the European Society of Gene and Cell Therapy. https://www.globenewswire.com/news-release/2018/10/16/1621781/0/en/Voyager-Therapeutics-Announces-Preclinical-Data-for-Huntington-s-Disease-and-Amyotrophic-Lateral-Sclerosis-Programs-at-the-Congress-of-the-European-Society-of-Gene-and-Cell-Therapy.html (2018).

  296. Bennett, C. F. & Swayze, E. E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259–293 (2010).

    CAS  PubMed  Google Scholar 

  297. Rinaldi, C. & Wood, M. J. A. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat. Rev. Neurol. 14, 9–21 (2018).

    CAS  PubMed  Google Scholar 

  298. Bennett, C. F. Therapeutic antisense oligonucleotides are coming of age. Annu. Rev. Med. 70, 307–321 (2019).

    CAS  PubMed  Google Scholar 

  299. Wolf, D. A. et al. Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery. JCI Insight 1, e85311 (2016).

    PubMed  PubMed Central  Google Scholar 

  300. Finkel, R. S. et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: a phase 2, open-label, dose-escalation study. Lancet 388, 3017–3026 (2016).

    CAS  PubMed  Google Scholar 

  301. Wang, N. et al. Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington’s disease. Nat. Med. 20, 536–541 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  302. Hammond, S. M. et al. Systemic peptide-mediated oligonucleotide therapy improves long-term survival in spinal muscular atrophy. Proc. Natl Acad. Sci. USA 113, 10962–10967 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  303. Min, H. S. et al. Systemic brain delivery of antisense oligonucleotides across the blood-brain barrier with a glucose-coated polymeric nanocarrier. Angew. Chem. Int. Ed. Engl. 59, 8173–8180 (2020).

    CAS  PubMed  PubMed Central  Google Scholar 

  304. Finkel, R. S. et al. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N. Engl. J. Med. 377, 1723–1732 (2017).

    CAS  PubMed  Google Scholar 

  305. Miller, T. M. et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol. 12, 435–442 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  306. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02623699 (2020).

  307. Southwell, A. L. et al. Huntingtin suppression restores cognitive function in a mouse model of Huntington’s disease. Sci. Transl Med. 10, eaar3959 (2018).

    PubMed  Google Scholar 

  308. Ducray, P. S. et al. AAN Presentation 2019: Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to support RG6042 dose selection in Huntington’s disease (HD). https://medically.roche.com/en/search/pdfviewer.2e65a24a-ffc3-4736-9154-17d3383c8a60.html?cid=slprxx1905nehdaan2019 (2019).

  309. Ducray, P. S. et al. Translational pharmacokinetic/pharmacodynamic (PK/PD) modeling strategy to support RG6042 dose selection in Huntington’s disease (HD) [abstract]. Neurology 92 (Suppl. 15), S16.005 (2019).

    Google Scholar 

  310. Schobel, S. A. et al. Motor, cognitive, and functional declines contribute to a single progressive factor in early HD. Neurology 89, 2495–2502 (2017).

    PubMed  PubMed Central  Google Scholar 

  311. Trundell, D. et al. F23 Validity, reliability, ability to detect change and meaningful within-patient change of the CUHDRS [abstract]. J. Neurol. Neurosurg. Psychiatry 89 (Suppl. 1), A48 (2018).

    Google Scholar 

  312. Hersch, S. et al. Multicenter, randomized, double-blind, placebo-controlled phase 1b/2a studies of WVE-120101 and WVE-120102 in patients with Huntington’s disease [abstract]. Neurology 88 (Suppl. 16), P2.006 (2017).

    Google Scholar 

  313. Datson, N. A. et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS ONE 12, e0171127 (2017).

    PubMed  PubMed Central  Google Scholar 

  314. Jiang, J. et al. Gain of toxicity from ALS/FTD-linked repeat expansions in C9ORF72 is alleviated by antisense oligonucleotides targeting GGGGCC-containing RNAs. Neuron 90, 535–550 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  315. Becanovic, K. et al. A SNP in the HTT promoter alters NF-κB binding and is a bidirectional genetic modifier of Huntington disease. Nat. Neurosci. 18, 807–816 (2015).

    CAS  PubMed  Google Scholar 

  316. Bhattacharyya, A. Identification and development of orally administered, CNS-penetrant small molecules that lower huntingtin protein levels by inducing a novel splicing event that alters the stability of huntingtin mRNA. https://chdifoundation.org/2019-conference/#bhattacharyya (2019).

  317. Naryshkin, N. A. et al. Motor neuron disease. SMN2 splicing modifiers improve motor function and longevity in mice with spinal muscular atrophy. Science 345, 688–693 (2014).

    CAS  PubMed  Google Scholar 

  318. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02240355 (2016).

  319. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02633709 (2018).

  320. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03032172 (2020).

  321. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02908685 (2020).

  322. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02913482 (2020).

  323. Liu, C. R. et al. Spt4 is selectively required for transcription of extended trinucleotide repeats. Cell 148, 690–701 (2012).

    CAS  PubMed  Google Scholar 

  324. Cheng, H. M. et al. Effects on murine behavior and lifespan of selectively decreasing expression of mutant huntingtin allele by supt4h knockdown. PLoS Genet. 11, e1005043 (2015).

    PubMed  PubMed Central  Google Scholar 

  325. Klug, A. The discovery of zinc fingers and their applications in gene regulation and genome manipulation. Annu. Rev. Biochem. 79, 213–231 (2010).

    CAS  PubMed  Google Scholar 

  326. Nemudryi, A. A., Valetdinova, K. R., Medvedev, S. P. & Zakian, S. M. TALEN and CRISPR/Cas genome editing systems: tools of discovery. Acta Naturae 6, 19–40 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  327. Adli, M. The CRISPR tool kit for genome editing and beyond. Nat. Commun. 9, 1911 (2018).

    PubMed  PubMed Central  Google Scholar 

  328. Malankhanova, T. B., Malakhova, A. A., Medvedev, S. P. & Zakian, S. M. Modern genome editing technologies in Huntington’s disease research. J. Huntington’s Dis. 6, 19–31 (2017).

    Google Scholar 

  329. Richard, G. F. et al. Highly specific contractions of a single CAG/CTG trinucleotide repeat by TALEN in yeast. PLoS ONE 9, e95611 (2014).

    PubMed  PubMed Central  Google Scholar 

  330. Fink, K. D. et al. Allele-specific reduction of the mutant huntingtin allele using transcription activator-like effectors in human Huntington’s disease fibroblasts. Cell Transplant. 25, 677–686 (2016).

    PubMed  Google Scholar 

  331. Heman-Ackah, S. M., Bassett, A. R. & Wood, M. J. Precision modulation of neurodegenerative disease-related gene expression in human iPSC-derived neurons. Sci. Rep. 6, 28420 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  332. Dabrowska, M., Juzwa, W., Krzyzosiak, W. J. & Olejniczak, M. Precise excision of the CAG tract from the huntingtin gene by Cas9 nickases. Front. Neurosci. 12, 75 (2018).

    PubMed  PubMed Central  Google Scholar 

  333. Ledford, H. CRISPR babies: when will the world be ready? Nature 570, 293–296 (2019).

    CAS  PubMed  Google Scholar 

  334. Zhang, X. H., Tee, L. Y., Wang, X. G., Huang, Q. S. & Yang, S. H. Off-target effects in CRISPR/Cas9-mediated genome engineering. Mol. Ther. Nucleic Acids 4, e264 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  335. Milone, M. C. & O’Doherty, U. Clinical use of lentiviral vectors. Leukemia 32, 1529–1541 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  336. Trundell, D. et al. Defining clinically meaningful change on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) (P1.8-043). Neurology 92 (Suppl. P1.8-043) (2019).

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Acknowledgements

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.

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  1. These authors contributed equally: Sarah J. Tabrizi, Michael D. Flower.

Authors and Affiliations

  1. Huntington’s Disease Centre, University College London, London, UK

    Sarah J. Tabrizi, Michael D. Flower & Edward J. Wild

  2. Department of Neurodegenerative Disease, Queen Square Institute of Neurology, University College London, London, UK

    Sarah J. Tabrizi, Michael D. Flower & Edward J. Wild

  3. UK Dementia Research Institute, University College London, London, UK

    Sarah J. Tabrizi & Michael D. Flower

  4. Departments of Neurology, Neuroscience and Pharmacology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Christopher A. Ross

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M.D.F and C.A.R researched data for the article, made substantial contributions to the discussion of the content of the article, wrote the article, and reviewed and edited the manuscript before submission. S.J.T. made a substantial contribution to the discussion of the content of the article, wrote the article, and reviewed and edited the manuscript before submission. E.J.W. made a substantial contribution to the discussion of the content of the article, and reviewed and edited the manuscript before submission.

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Competing interests

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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Glossary

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.

Loop-outs

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.

microRNA

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

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