Review Article

Multimodal treatment strategies in Huntington’s disease

Rajib Dutta*

Published: 15 July, 2021 | Volume 5 - Issue 2 | Pages: 072-082

Huntington’s disease (HD) is an incurable neurodegenerative disease that causes involuntary movements, emotional lability, and cognitive dysfunction. HD symptoms usually develop between ages 30 and 50, but can appear as early as 2 or as late as 80 years. Currently no neuroprotective and neurorestorative interventions are available. Early multimodal intervention in HD is only possible if the genetic diagnosis is made early. Early intervention in HD is only possible if genetic diagnosis is made at the disease onset or when mild symptoms manifest. Growing evidence and understanding of HD pathomechanism has led researchers to new therapeutic targets. Here, in this article we will talk about the multimodal treatment strategies and recent advances made in this field which can be used to target the HD pathogenesis at its most proximal level.

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Huntington’s disease; Genetic; Pathogenesis; Therapeutic; Multimodal; Treatment


  1. Bates GP, Dorsey R, Gusella JF, Hayden MR, Kay C, et al. Huntington disease. Nat Rev Dis Primers. 2015; 1: 15005. PubMed: https://pubmed.ncbi.nlm.nih.gov/27188817/
  2. Finkbeiner S. Huntington's Disease. Cold Spring Harb Perspect Biol. 2011; 3: a007476. PubMed: https://pubmed.ncbi.nlm.nih.gov/21441583/
  3. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group. Cell. 1993 Mar 26; 72: 971-983. PubMed: https://pubmed.ncbi.nlm.nih.gov/8458085/
  4. Walker FO. Huntington's disease. Lancet. 2007 Jan 20; 369: 218-228. PubMed: https://pubmed.ncbi.nlm.nih.gov/17240289/
  5. Gilliam TC, Tanzi RE, Haines JL, Bonner TI, Faryniarz AG, et al. Localization of the Huntington's disease gene to a small segment of chromosome 4 flanked by D4S10 and the telomere. Cell. 1987; 50: 565-571. PubMed: https://pubmed.ncbi.nlm.nih.gov/2886227/
  6. Ghosh R, Tabrizi SJ. Huntington disease. Handb Clin Neurol. 2018; 147: 255-278. PubMed: https://pubmed.ncbi.nlm.nih.gov/29325616/
  7. Lee JM, Ramos EM, Lee JH, Gillis T, Mysore JS, et al. CAG repeat expansion in Huntington disease determines age at onset in a fully dominant fashion. Neurology. 2012; 78: 690-695. PubMed: https://pubmed.ncbi.nlm.nih.gov/22323755/
  8. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, et al. Phenotypic characterization of individuals with 30-40 CAG repeats in the Huntington disease (HD) gene reveals HD cases with 36 repeats and apparently normal elderly individuals with 36-39 repeats. Am J Hum Genet. 1996; 59: 16-22. PubMed: https://pubmed.ncbi.nlm.nih.gov/8659522/
  9. Kremer B, Almqvist E, Theilmann J, Spence N, Telenius H, et al. Sex-dependent mechanisms for expansions and contractions of the CAG repeat on affected Huntington disease chromosomes. Am J Hum Genet. 1995; 57: 343-350. PubMed: https://pubmed.ncbi.nlm.nih.gov/7668260/
  10. Ranen NG, Stine OC, Abbott MH, Sherr M, Codori AM, et al. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington disease. Am J Hum Genet. 1995; 57: 593-602. PubMed: https://pubmed.ncbi.nlm.nih.gov/7668287/
  11. Trottier Y, Biancalana V, Mandel JL. Instability of CAG repeats in Huntington's disease: relation to parental transmission and age of onset. J Med Genet. 1994; 31: 377-382. PubMed: https://pubmed.ncbi.nlm.nih.gov/8064815/
  12. Myers RH, MacDonald ME, Koroshetz WJ, Duyao MP, Ambrose CM, et al. De novo expansion of a (CAG)n repeat in sporadic Huntington's disease. Nat Genet. 1993; 5: 168-173. PubMed: https://pubmed.ncbi.nlm.nih.gov/8252042/
  13. Semaka A, Creighton S, Warby S, Hayden MR. Predictive testing for Huntington disease: interpretation and significance of intermediate alleles. Clin Genet. 2006; 70: 283-294. PubMed: https://pubmed.ncbi.nlm.nih.gov/16965319/
  14. Andrew SE, Goldberg YP, Kremer B, Telenius H, Theilmann J, et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nat Genet. 1993; 4: 398-403. PubMed: https://pubmed.ncbi.nlm.nih.gov/8401589/
  15. Genetic Modifiers of Huntington’s Disease (GeM-HD) Consortium. Identification of Genetic Factors that Modify Clinical Onset of Huntington's Disease. Cell. 2015; 162: 516-526. PubMed: https://pubmed.ncbi.nlm.nih.gov/26232222/
  16. Rawlins MD, Wexler NS, Wexler AR, Tabrizi SJ, Douglas I, et al. The prevalence of huntington’s disease. Neuroepidemiology. 2016; 46: 144–153. PubMed: https://pubmed.ncbi.nlm.nih.gov/26824438/
  17. Pringsheim T, Wiltshire K, Day L, Dykeman J, Steeves T, et al. The incidence and prevalence of huntington’s disease: a systematic review and meta-analysis. Mov Disord. 2012; 27: 1083–1091. PubMed: https://pubmed.ncbi.nlm.nih.gov/22692795/
  18. Bashir H, Jankovic J. Treatment options for chorea. Expert Rev Neurother. 2018; 18: 51–63. PubMed: https://pubmed.ncbi.nlm.nih.gov/29120264/
  19. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in huntington’s disease. Physiol Rev.2010; 90: 905–981. PubMed: https://pubmed.ncbi.nlm.nih.gov/20664076/
  20. Arrasate M, Finkbeiner S. Protein aggregates in huntington’s disease. Exp Neurol. 2012; 238: 1–11. PubMed: https://pubmed.ncbi.nlm.nih.gov/22200539/
  21. Neueder A, Landles C, Ghosh R, Howland D, Myers RH, et al. The pathogenic exon 1 HTT protein is produced by incomplete splicing in huntington’s disease patients. Sci Rep. 2017; 7: 1307. PubMed: https://pubmed.ncbi.nlm.nih.gov/28465506/
  22. Slow EJ, van Raamsdonk J, Rogers D, Coleman SH, Graham RK, et al. Selective striatal neuronal loss in a YAC128 mouse model of Huntington disease. Hum Mol Genet. 2003; 12: 1555–1567. PubMed: https://pubmed.ncbi.nlm.nih.gov/12812983/
  23. Slow EJ, Graham RK, Osmand AP, Devon RS, Lu G, et al. Absence of behavioral abnormalities and neurodegeneration in vivo despite widespread neuronal huntingtin inclusions. Proc Natl Acad Sci U S A. 2005; 102: 11402–11407. PubMed: https://pubmed.ncbi.nlm.nih.gov/16076956/
  24. Sica RE. Could astrocytes be the primary target of an offending agent causing the primary degenerative diseases of the human central nervous system? A hypothesis. Med Hypotheses. 2015; 84: 481–489. PubMed: https://pubmed.ncbi.nlm.nih.gov/25697116/
  25. Fjodorova M, Louessard M, Li Z, De La Fuente DC, Dyke E, et al. CTIP2-Regulated Reduction in PKA-Dependent DARPP32 Phosphorylation in Human Medium Spiny Neurons: Implications for Huntington Disease. Stem Cell Reports. 2019; 13: 448-457. PubMed: https://pubmed.ncbi.nlm.nih.gov/31447328/
  26. Wild EJ, Tabrizi SJ. Therapies targeting DNA and RNA in Huntington's disease [published correction appears in Lancet Neurol. 2017 Dec; 16: 954]. Lancet Neurol. 2017; 16: 837-847. PubMed: https://pubmed.ncbi.nlm.nih.gov/28920889/
  27. Crooke ST. Molecular Mechanisms of Antisense Oligonucleotides. Nucleic Acid Ther. 2017; 27: 70-77. PubMed: https://pubmed.ncbi.nlm.nih.gov/28080221/
  28. Du L, Kayali R, Bertoni C, Fike F, Hu H, et al. Arginine-rich cell-penetrating peptide dramatically enhances AMO-mediated ATM aberrant splicing correction and enables delivery to brain and cerebellum. Hum Mol Genet 2011; 20: 3151–3160. PubMed: https://pubmed.ncbi.nlm.nih.gov/21576124/
  29. Aguiar S, van der Gaag B, Cortese FAB. RNAi mechanisms in Huntington's disease therapy: siRNA versus shRNA. Transl Neurodegener. 2017; 6: 30. PubMed: https://pubmed.ncbi.nlm.nih.gov/29209494/
  30. Pfister EL, DiNardo N, Mondo E, Borel F, Conroy F, et al. Artificial miRNAs Reduce Human Mutant Huntingtin Throughout the Striatum in a Transgenic Sheep Model of Huntington's Disease. Hum Gene Ther. 2018; 29: 663-673. PubMed: https://pubmed.ncbi.nlm.nih.gov/29207890/
  31. Sah DW, Aronin N. Oligonucleotide therapeutic approaches for Huntington disease. J Clin Invest. 2011; 121: 500-507. PubMed: https://pubmed.ncbi.nlm.nih.gov/21285523/
  32. Boudreau RL, McBride JL, Martins I, Shen S, Xing Y, et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Mol Ther. 2009; 17: 1053–1063. PubMed: https://pubmed.ncbi.nlm.nih.gov/19240687/
  33. McBride JL, Pitzer MR, Boudreau RL, Dufour B, Hobbs T, et al. Preclinical safety of RNAi mediated HTT suppression in the rhesus macaque as a potential therapy for Huntington’s disease. Mol Ther. 2011; 19: 2152–2162. PubMed: https://pubmed.ncbi.nlm.nih.gov/22031240/
  34. Qu Y, Liu Y, Noor AF, Tran J, Li R. Characteristics and advantages of adeno-associated virus vector-mediated gene therapy for neurodegenerative diseases. Neural Regen Res. 2019; 14: 931-938. PubMed: https://pubmed.ncbi.nlm.nih.gov/30761996/
  35. Merkel SF, Andrews AM, Lutton EM, Mu D, Hudry E, et al. Trafficking of adeno-associated virus vectors across a model of the blood-brain barrier; a comparative study of transcytosis and transduction using primary human brain endothelial cells. J Neurochem. 2017; 140: 216-230. PubMed: https://pubmed.ncbi.nlm.nih.gov/27718541/
  36. Dufour BD, Smith CA, Clark RL, Walker TR, McBride JL. Intrajugular vein delivery of AAV9-RNAi prevents neuropathological changes and weight loss in huntington’s disease mice. Mol Ther. 2014; 22: 797–810. PubMed: https://pubmed.ncbi.nlm.nih.gov/24390280/
  37. Matsuzaki Y, Konno A, Mochizuki R, Shinohara Y, Nitta K, et al. Intravenous administration of the adeno-associated virus-PHP.B. capsid fails to upregulate transduction efficiency in the marmoset brain. Neurosci Lett. 2018; 665: 182–188. PubMed: https://pubmed.ncbi.nlm.nih.gov/29175632/
  38. Marco S, Murillo A, Pérez-Otaño I. RNAi-Based GluN3A Silencing Prevents and Reverses Disease Phenotypes Induced by Mutant huntingtin. Mol Ther. 2018; 26: 1965-1972. PubMed: https://pubmed.ncbi.nlm.nih.gov/29914757/
  39. Matthes F, Massari S, Bochicchio A, Schorpp K, Schilling J, et al. Reducing Mutant Huntingtin Protein Expression in Living Cells by a Newly Identified RNA CAG Binder. ACS Chem Neurosci. 2018; 9: 1399-1408. PubMed: https://pubmed.ncbi.nlm.nih.gov/29506378/
  40. Sava V, Fihurka O, Khvorova A, Sanchez-Ramos J. Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington's disease gene expression following intranasal administration. Nanomedicine. 2020; 24: 102119. PubMed: https://pubmed.ncbi.nlm.nih.gov/31666200/
  41. Miniarikova J, Zimmer V, Martier R, Brouwers CC, Pythoud C, 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. 2017; 24: 630-639. PubMed: https://pubmed.ncbi.nlm.nih.gov/28771234/
  42. Keskin S, Brouwers CC, Sogorb-Gonzalez M, Martier R, Depla JA, et al. AAV5-miHTT Lowers Huntingtin mRNA and Protein without Off-Target Effects in Patient-Derived Neuronal Cultures and Astrocytes. Mol Ther Methods Clin Dev. 2019; 15: 275-284. PubMed: https://pubmed.ncbi.nlm.nih.gov/31737741/
  43. Rinaldi C, Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol.2017; 14: 9–21. PubMed: https://pubmed.ncbi.nlm.nih.gov/29192260/
  44. Ionis Pharmaceuticals. IONIS-HTT Rx (RG6042) top-line data demonstrate significant reductions of disease-causing mutant huntingtin protein in people with huntington’s disease. 2019. http://ir.ionispharma.com/node/23401/pdf
  45. Datson NA, González-Barriga A, Kourkouta E, Weij R, van de Giessen J, et al. The expanded CAG repeat in the huntingtin gene as target for therapeutic RNA modulation throughout the HD mouse brain. PLoS One. 2017; 12: e0171127. PubMed: https://pubmed.ncbi.nlm.nih.gov/28182673/
  46. Keeler AM, Sapp E, Chase K, Sottosanti E, Danielson E, et al. Cellular Analysis of Silencing the Huntington's Disease Gene Using AAV9 Mediated Delivery of Artificial Micro RNA into the Striatum of Q140/Q140 Mice. J Huntingtons Dis. 2016; 5: 239-248. PubMed: https://pubmed.ncbi.nlm.nih.gov/27689620/
  47. Mathkar PP, Suresh D, Dunn J, Tom CM, Mattis VB. Characterization of Neurodevelopmental Abnormalities in iPSC-Derived Striatal Cultures from Patients with Huntington's Disease. J Huntingtons Dis. 2019; 8: 257-269. PubMed: https://pubmed.ncbi.nlm.nih.gov/31381521/
  48. Geary RS, Norris D, Yu R, Bennett CF. Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev.2015; 87: 46–51. PubMed: https://pubmed.ncbi.nlm.nih.gov/25666165/
  49. Kim MS, Kini AG. Engineering and Application of Zinc Finger Proteins and TALEs for Biomedical Research. Mol Cells. 2017; 40: 533-541. PubMed: https://pubmed.ncbi.nlm.nih.gov/28835021/
  50. Mittelman D, Moye C, Morton J, Sykoudis K, Lin Y, et al. Zinc-finger directed double-strand breaks within CAG repeat tracts promote repeat instability in human cells. Proc Natl Acad Sci U S A. 2009; 106: 9607–9612. PubMed: https://pubmed.ncbi.nlm.nih.gov/19482946/
  51. Garriga-Canut M, Agustín-Pavón C, Herrmann F, Sánchez A, Dierssen M, et al. Synthetic zinc finger repressors reduce mutant huntingtin expression in the brain of R6/2 mice. Proc Natl Acad Sci U S A. 2012; 109: E3136–45. PubMed: https://pubmed.ncbi.nlm.nih.gov/23054839/
  52. Cubbon A, Ivancic-Bace I, Bolt EL. CRISPR-Cas immunity, DNA repair and genome stability. Biosci Rep. 2018; 38: BSR20180457. PubMed: https://pubmed.ncbi.nlm.nih.gov/30209206/
  53. Pickar-Oliver A, Gersbach CA. The next generation of CRISPR-Cas technologies and applications. Nat Rev Mol Cell Biol. 2019; 20: 490-507. PubMed: https://pubmed.ncbi.nlm.nih.gov/31147612/
  54. Nambiar TS, Billon P, Diedenhofen G, Hayward SB, Taglialatela A, et al. Stimulation of CRISPR-mediated homology-directed repair by an engineered RAD18 variant. Nat Commun. 2019; 10: 3395. PubMed: https://pubmed.ncbi.nlm.nih.gov/31363085/
  55. Yang S, Chang R, Yang H, Zhao T, Hong Y, et al. CRISPR/Cas9-mediated gene editing ameliorates neurotoxicity in mouse model of huntington’s disease. J Clin Invest. 2017; 127: 2719–2724. PubMed: https://pubmed.ncbi.nlm.nih.gov/28628038/
  56. Shin JW, Kim KH, Chao MJ, Atwal RS, Gillis T, et al. Permanent inactivation of Huntington's disease mutation by personalized allele-specific CRISPR/Cas9. Hum Mol Genet. 2016; 25: 4566-4576. PubMed: https://pubmed.ncbi.nlm.nih.gov/28172889/
  57. Pan Y, Daito T, Sasaki Y, Chung YH, Xing X, et al. Inhibition of DNA Methyltransferases Blocks Mutant Huntingtin-Induced Neurotoxicity. Sci Rep. 2016; 21: 33766. PubMed: https://pubmed.ncbi.nlm.nih.gov/27649847/
  58. Luthi-Carter R, Taylor DM, Pallos J, Lambert E, Amore A, et al. SIRT2 inhibition achieves neuroprotection by decreasing sterol biosynthesis. Proc Natl Acad Sci USA. 2010; 107: 7927–7932. PubMed: https://pubmed.ncbi.nlm.nih.gov/20378838/
  59. Zuccato C, Valenza M, Cattaneo E. Molecular mechanisms and potential therapeutical targets in Huntington’s disease. Physiol Rev. 2010; 90: 905–981. PubMed: https://pubmed.ncbi.nlm.nih.gov/20664076/
  60. Chopra V, Quinti L, Kim J, Vollor L, Narayanan KL, et al. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse models. Cell Rep. 2012; 2: 1492-1497. PubMed: https://pubmed.ncbi.nlm.nih.gov/23200855/
  61. Jeong H, Then F, Melia TJ Jr, Mazzulli JR, Cui L, et al. Acetylation targets mutant huntingtin to autophagosomes for degradation. Cell 2009; 137: 60–72. PubMed: https://pubmed.ncbi.nlm.nih.gov/19345187/
  62. Zhang F, Wang S, Gan L, Vosler PS, Gao Y, et al. Protective effects and mechanisms of sirtuins in the nervous system. Prog Neurobiol 2011; 95: 373–395. PubMed: https://pubmed.ncbi.nlm.nih.gov/21930182/
  63. Pallos J, Bodai L, Lukacsovich T, Purcell JM, Steffan JS, et al. Inhibition of specific HDACs and sirtuins suppresses pathogenesis in a Drosophila model of Huntington’s disease. Hum Mol Genet 2008; 17: 3767–3775. PubMed: https://pubmed.ncbi.nlm.nih.gov/18762557/
  64. Napper AD, Hixon J, McDonagh T, Keavey K, Pons JP, et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SirT1. J Med Chem 2005; 48: 8045–854. PubMed: https://pubmed.ncbi.nlm.nih.gov/16335928/
  65. Smith MR, Syed A, Lukacsovich T, Purcell J, Barbaro BA, et al. Sirtuin 1 inhibition alleviates pathology in multiple animal and cell models of Huntington’s disease. Hum Mol Genet 2014; 23: 2995–3007. PubMed: https://pubmed.ncbi.nlm.nih.gov/24436303/
  66. Reilmann R, Squitieri F, Priller J, et al. N02 Safety And Tolerability Of Selisistat For The Treatment Of Huntington’s Disease: Results From A Randomised, Double-blind, Placebo-controlled Phase Ii Trial. J Neurol Neurosurg Psychiatry. 2014; 85: A102.
  67. Deb A, Frank S, Testa CM. New symptomatic therapies for Huntington disease. Handb Clin Neurol. 2017; 144: 199-207. PubMed: https://pubmed.ncbi.nlm.nih.gov/28947118/
  68. Johanssen T, Suphantarida N, Donnelly PS, Liu XM, Petrou S, et al. PBT2 inhibits glutamate-induced excitotoxicity in neurons through metal-mediated preconditioning. Neurobiol Dis. 2015; 81: 176-185. PubMed: https://pubmed.ncbi.nlm.nih.gov/25697105/
  69. Huntington Study Group Reach 2HD Investigators. Safety, tolerability, and efficacy of PBT2 in huntington’s disease: a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015; 14: 39–47. PubMed: https://pubmed.ncbi.nlm.nih.gov/25467848/
  70. Prana Biotech. 2015. FDA end of phase 2 status update. 2019. http://pranabio.com/wp-content/uploads/2015/02/150213_FDA-notification-FINAL.pdf
  71. Rocha NP, Ribeiro FM, Furr-Stimming E, Teixeira AL. Neuroimmunology of Huntington's Disease: Revisiting Evidence from Human Studies. Mediators Inflamm. 2016; 2016: 8653132. PubMed: https://pubmed.ncbi.nlm.nih.gov/27578922/
  72. Crotti A, Benner C, Kerman BE, Gosselin D, Lagier-Tourenne C, et al. Mutant huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci. 2014; 17: 513–521. PubMed: https://pubmed.ncbi.nlm.nih.gov/24584051/
  73. Garcia-Miralles M, Yusof NABM, Tan JY, Radulescu CI, Sidik H, et al. Laquinimod Treatment Improves Myelination Deficits at the Transcriptional and Ultrastructural Levels in the YAC128 Mouse Model of Huntington Disease. Mol Neurobiol. 2019; 56: 4464-4478. PubMed: https://pubmed.ncbi.nlm.nih.gov/30334188/
  74. Ellrichmann G, Blusch A, Fatoba O, Brunner J, Reick C, et al. Laquinimod treatment in the R6/2 mouse model Sci Rep. 2017; 7: 4947. PubMed: https://pubmed.ncbi.nlm.nih.gov/28694434/
  75. Garcia-Miralles M, Hong X, Tan LJ, Caron NS, Huang Y, et al. Laquinimod rescues striatal, cortical and white matter pathology and results in modest behavioural improvements in the YAC128 model of Huntington disease. Sci Rep. 2016; 6: 31652. PubMed: https://pubmed.ncbi.nlm.nih.gov/27528441/
  76. Ehrnhoefer DE, Caron NS, Deng Y, Qiu X, Tsang M, et al. Laquinimod decreases Bax expression and reduces caspase-6 activation in neurons. Exp Neurol. 2016; 283: 121-128. PubMed: https://pubmed.ncbi.nlm.nih.gov/27296315/
  77. Rodrigues FB, Wild EJ. Huntington's Disease Clinical Trials Corner: August 2018. J Huntingtons Dis. 2018; 7: 279-286. PubMed: https://pubmed.ncbi.nlm.nih.gov/30103342/
  78. Rodrigues FB, Ferreira JJ, Wild EJ. Huntington's Disease Clinical Trials Corner: June 2019. J Huntingtons Dis. 2019; 8: 363-371. PubMed: https://pubmed.ncbi.nlm.nih.gov/31381524/
  79. https://huntingtonsdiseasenews.com/2018/04/26/aan2018-phase-2-trial-targets-loss-brain-volume-huntingtons/
  80. Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington's Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med. 2017; 7: a024240. PubMed: https://pubmed.ncbi.nlm.nih.gov/27940602/
  81. Sahlholm K, Århem P, Fuxe K, Marcellino D. The dopamine stabilizers ACR16 and (-)-OSU6162 display nanomolar affinities at the σ-1 receptor. Mol Psychiatry. 2013; 18: 12-14. PubMed: https://pubmed.ncbi.nlm.nih.gov/22349783/
  82. Waters S, Tedroff J, Ponten H, Klamer D, Sonesson C, et al. Pridopidine: Overview of Pharmacology and Rationale for its Use in Huntington's Disease. J Huntingtons Dis. 2018; 7: 1-16. PubMed: https://pubmed.ncbi.nlm.nih.gov/29480206/
  83. Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, et al. Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in huntington’s disease. Proc Natl Acad Sci USA. 2005; 102: 2602–2607. PubMed: https://pubmed.ncbi.nlm.nih.gov/15695335/
  84. Hyrskyluoto A, Pulli I, Törnqvist K, Ho TH, Korhonen L, et al. Sigma-1 receptor agonist PRE084 is protective against mutant huntingtin-induced celldegeneration: involvement of calpastatin and the NF-κB pathway.Cell Death Dis. 2013; 4: e646. PubMed: https://pubmed.ncbi.nlm.nih.gov/23703391/
  85. Smith-Dijak AI, Nassrallah WB, Zhang LYJ, Geva M, Hayden MR, et al. Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease. Front Cell Neurosci. 2019; 13: 209. PubMed: https://pubmed.ncbi.nlm.nih.gov/31156395/
  86. Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, et al. Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor. Neurobiology of Disease. 2019; 129; 118–129. PubMed: https://pubmed.ncbi.nlm.nih.gov/31108174/
  87. Kusko R, Dreymann J, Ross J, et al. Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse. Mol Neurodegener. 2018; 13: 25.
  88. Garcia-Miralles M, Geva M, Tan JY, Mohammad Yusof NABM, Cha Y, et al. Early pridopidine treatment improves behavioral and transcriptional deficits in YAC128 Huntington disease mice. JCI Insight. 2017; 2: e95665. PubMed: https://pubmed.ncbi.nlm.nih.gov/29212949/
  89. Reilmann R, McGarry A, Grachev ID, 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. 2019; 18: 165-176. PubMed: https://pubmed.ncbi.nlm.nih.gov/30563778/
  90. Jokinen EM, Postila PA, Ahinko M, Niinivehmas S, Pentikäinen OT. Fragment- and negative image-based screening of phosphodiesterase 10A inhibitors. Chem Biol Drug Des. 2019; 94: 1799-1812. PubMed: https://pubmed.ncbi.nlm.nih.gov/31260165/
  91. Diggle CP, Sukoff Rizzo SJ, Popiolek M, et al. Biallelic Mutations in PDE10A Lead to Loss of Striatal PDE10A and a Hyperkinetic Movement Disorder with Onset in Infancy. Am J Hum Genet. 2016; 98: 735-743. PubMed: https://pubmed.ncbi.nlm.nih.gov/27058446/
  92. Harada A, Suzuki K, Kimura H. TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington's Disease. J Pharmacol Exp Ther. 2017; 360: 75-83.
  93. Beaumont V, Zhong S, Lin H, Hinttala R, Schülke JP, et al. Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models. Neuron. 2016; 92: 1220-1237.
  94. Chang WT, Puspitasari F, Garcia-Miralles M, Yeow LY, Tay HC, et al. Connectomic imaging reveals Huntington-related pathological and pharmaceutical effects in a mouse model. NMR Biomed. 2018; 31: e4007. PubMed: https://pubmed.ncbi.nlm.nih.gov/30260561/
  95. Chidambaram SB, Vijayan R, Sekar S, Mani S, Rajamani B, et al. Simultaneous blockade of NMDA receptors and PARP-1 activity synergistically alleviate immunoexcitotoxicity and bioenergetics in 3-nitropropionic acid intoxicated mice: Evidences from memantine and 3-aminobenzamide interventions. Eur J Pharmacol. 2017; 803: 148-158. PubMed: https://pubmed.ncbi.nlm.nih.gov/28322842/
  96. Mahfooz K, Marco S, Martínez-Turrillas R, Raja MK, Pérez-Otaño I, et al. GluN3A promotes NMDA spiking by enhancing synaptic transmission in Huntington's disease models. Neurobiol Dis. 2016; 93: 47-56. PubMed: https://pubmed.ncbi.nlm.nih.gov/27072890/
  97. Arbez N, Roby E, Akimov S, Eddings C, Ren M, et al. Cysteamine Protects Neurons from Mutant Huntingtin Toxicity. J Huntingtons Dis. 2019; 8: 129-143. PubMed: https://pubmed.ncbi.nlm.nih.gov/30856117/
  98. Borrell-Pagès M, Canals JM, Cordelières FP, Parker JA, Pineda JR, et al. Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest. 2006; 116: 1410-1424. PubMed: https://pubmed.ncbi.nlm.nih.gov/16604191/
  99. Verny C, Bachoud-Lévi AC, Durr A, Goizet C, Azulay JP, et al. A randomized, double-blind, placebo-controlled trial evaluating cysteamine in Huntington's disease. Mov Disord. 2017; 32: 932-936. PubMed: https://pubmed.ncbi.nlm.nih.gov/28436572/
  100. Colpo GD, Ascoli BM, Wollenhaupt-Aguiar B, Pfaffenseller B, Silva EG, et al. Mesenchymal stem cells for the treatment of neurodegenerative and psychiatric disorders. An Acad Bras Cienc. 2015; 87: 1435–1449. PubMed: https://pubmed.ncbi.nlm.nih.gov/26247151/
  101. Wu TT, Su FJ, Feng YQ, Liu B, Li MY, et al. Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice. Stem Cells. 2020; 38: 218-230. PubMed: https://pubmed.ncbi.nlm.nih.gov/31648394/
  102. Elbaz EM, Helmy HS, El-Sahar AE, Saad MA, Sayed RH. Lercanidipine boosts the efficacy of mesenchymal stem cell therapy in 3-NP-induced Huntington's disease model rats via modulation of the calcium/calcineurin/NFATc4 and Wnt/β-catenin signalling pathways. Neurochem Int. 2019; 131: 104548. PubMed: https://pubmed.ncbi.nlm.nih.gov/31539560/
  103. Yu-Taeger L, Stricker-Shaver J, Arnold K, Bambynek-Dziuk P, Novati A, et al. Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease. Cells. 2019; 8: 595. PubMed: https://pubmed.ncbi.nlm.nih.gov/31208073/
  104. Cho IK, Hunter CE, Ye S, Pongos AL, Chan AWS. Combination of stem cell and gene therapy ameliorates symptoms in Huntington's disease mice. NPJ Regen Med. 2019; 4: 7. PubMed: https://pubmed.ncbi.nlm.nih.gov/30937182/
  105. Eskandari N, Boroujeni ME, Abdollahifar MA, Piryaei A, Khodagholi F, et al. Transplantation of human dental pulp stem cells compensates for striatal atrophy and modulates neuro-inflammation in 3-nitropropionic acid rat model of Huntington's disease. 2020. Neurosci Res. 2020; S0168-0102(20)30505-8. PubMed: https://pubmed.ncbi.nlm.nih.gov/33359180/
  106. Bayat AH, Saeidikhoo S, Ebrahimi V, Mesgar S, Joneidi M, et al. Bilateral striatal transplantation of human olfactory stem cells ameliorates motor function, prevents necroptosis-induced cell death and improves striatal volume in the rat model of Huntington's disease. J Chem Neuroanat. 2021; 112: 101903. PubMed: https://pubmed.ncbi.nlm.nih.gov/33278568/
  107. Yoon Y, Kim HS, Hong CP, Li E, Jeon I, et al. Neural Transplants From Human Induced Pluripotent Stem Cells Rescue the Pathology and Behavioral Defects in a Rodent Model of Huntington's Disease. Front Neurosci. 2020; 14: 558204. PubMed: https://pubmed.ncbi.nlm.nih.gov/33071737/
  108. Besusso D, Schellino R, Boido M, Belloli S, Parolisi R, et al. Stem Cell-Derived Human Striatal Progenitors Innervate Striatal Targets and Alleviate Sensorimotor Deficit in a Rat Model of Huntington Disease. Stem Cell Reports. 2020; 14: 876-891. PubMed: https://pubmed.ncbi.nlm.nih.gov/32302555/
  109. Giampà C, Alvino A, Magatti M, Silini AR, Cardinale A, et al. Conditioned medium from amniotic cells protects striatal degeneration and ameliorates motor deficits in the R6/2 mouse model of Huntington's disease. J Cell Mol Med. 2019; 23: 1581-1592. PubMed: https://pubmed.ncbi.nlm.nih.gov/30585395/
  110. Adil MM, Gaj T, Rao AT, Kulkarni RU, Fuentes CM, et al. hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model. Stem Cell Reports. 2018; 10: 1481-1491. PubMed: https://pubmed.ncbi.nlm.nih.gov/29628395/
  111. Ebrahimi MJ, Aliaghaei A, Boroujeni ME, Khodagholi F, Meftahi G, et al. Human Umbilical Cord Matrix Stem Cells Reverse Oxidative Stress-Induced Cell Death and Ameliorate Motor Function and Striatal Atrophy in Rat Model of Huntington Disease. Neurotox Res. 2018; 34: 273-284. PubMed: https://pubmed.ncbi.nlm.nih.gov/29520722/
  112. Zhu G, Geng X, Tan Z, Chen Y, Zhang R, et al. Characteristics of Globus Pallidus Internus Local Field Potentials in Hyperkinetic Disease. Front Neurol. 2018; 9: 934. PubMed: https://pubmed.ncbi.nlm.nih.gov/30455666/
  113. Ferrea S, Groiss SJ, Elben S, Hartmann CJ, Dunnett SB, et al. Pallidal deep brain stimulation in juvenile Huntington's disease: local field potential oscillations and clinical data. J Neurol. 2018; 265: 1573-1579. PubMed: https://pubmed.ncbi.nlm.nih.gov/29725840/
  114. Zittel S, Tadic V, Moll CKE, Bäumer T, Fellbrich A, et al. Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington's disease. Parkinsonism Relat Disord. 2018; 51: 96-100. PubMed: https://pubmed.ncbi.nlm.nih.gov/29486999/
  115. Gonzalez V, Cif L, Biolsi B, Seychelles A, Sanrey E, et al. Deep brain stimulation for Huntington’s disease: long-term results of a prospective open label study. J Neurosurg. 2014; 121: 114–122. PubMed: https://pubmed.ncbi.nlm.nih.gov/24702329/
  116. Wojtecki L, Groiss SJ, Ferrea S, Elben S, Hartmann CJ, et al. A prospective pilot trial for pallidal deep brain stimulation in huntington’s disease. Front Neurol. 2015; 6: 177. PubMed: https://pubmed.ncbi.nlm.nih.gov/26347707/
  117. Yin Z, Bai Y, Zhang H, Liu H, Hu W, et al. An individual patient analysis of the efficacy of using GPi-DBS to treat Huntington's disease. Brain Stimul. 2020; 13: 1722-1731. PubMed: https://pubmed.ncbi.nlm.nih.gov/33038596/
  118. Sanrey E, Macioce V, Gonzalez V, Cif L, Cyprien F, et al. Does pallidal neuromodulation influence cognitive decline in Huntington's disease? J Neurol. 2021; 268: 613-622. PubMed: https://pubmed.ncbi.nlm.nih.gov/32886253/
  119. Lee M, Im W, Kim M. Exosomes as a potential messenger unit during heterochronic parabiosis for amelioration of Huntington's disease. Neurobiol Dis. 2021; 155: 105374. PubMed: https://pubmed.ncbi.nlm.nih.gov/33940179/
  120. Drew CJG, Sharouf F, Randell E, Brookes-Howell L, Smallman K, et al. Protocol for an open label: phase I trial within a cohort of foetal cell transplants in people with Huntington's disease. Brain Commun. 2021; 3: fcaa230. PubMed: https://pubmed.ncbi.nlm.nih.gov/33543141/

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