A Comprehensive Review of Pharmacological and Non-Pharmacological Therapies for Huntington’s Disease
Main Article Content
Abstract
Over the last years, an increased interest in pharmacological and non-pharmacological therapeutic approaches have increased in HD research, at the moment HD remains a non-curable disease and current approaches involve symptomatic disease treatment. The systematic review identifies studies that have investigated pharmacological and non-pharmacological interventions, in HD individuals and mouse models to identify the clinical impact, regarding i) silencing and reduction of mHTT, ii) safety, efficiency and toxicity of antisense nucleotides, zinc finger proteins, CRISPR-Cas9 and transcription activator-like effector nuclease, iii) genetic modifiers contributing to early or delayed HD onset and, iv) importance of physical activity on motor and cognitive function. A systematic search of PubMed and Directory of Open Access Journal was performed by two independent reviewers using specific search term criteria for studies. The search period included studies from 2000 until 2024. The identified abstracts were screened and studies within the review fulfilled predetermined inclusion criteria. Furthermore, reference screening of included studies was also conducted. A total of forty-two studies were included. Most pharmacological studies identified that oligonucleotides, zinc finger proteins and transcription activator-like effector nuclease, reduced mHTT and HD mRNA, decreased toxicity and allele-specific targeting to prevent wild-type HTT targeting. In addition, studies involving medication such as Tetrabenazine showed to suppress HD-related chorea symptoms, while Atomoxetine did not suppress symptoms and Pridopidine showed an efficiency regarding motor symptoms. The safety and efficacy of these drugs are similar to that of other studies. Physical activity studies demonstrated that HD patients showed improvement in their gait and motor functions, an increase in cognitive function and quality of life, and a decrease in anxiety and depression, this indicates the beneficial health effects of physical activity in HD. However, further research is required to assess the full impact of pharmacological and non-pharmacological approaches in larger clinical trials assessing safety, feasibility and efficacy within HD mouse models and the HD population.
Keywords:
Huntington’s disease, Pharmacological, Non-pharmacological, Antisense Oligonucleotides, Genetic Modifiers, Biomarkers, Physical Activity
Article Details
How to Cite
CHRISTODOULOU, Christiana C.; ARISTEIDOU, Dimitriana; ZAMBA-PAPANICOLAOU, Eleni.
A Comprehensive Review of Pharmacological and Non-Pharmacological Therapies for Huntington’s Disease.
Medical Research Archives, [S.l.], v. 13, n. 2, feb. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6279>. Date accessed: 17 mar. 2025.
doi: https://doi.org/10.18103/mra.v13i2.6279.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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2. Jacob, E. L., Gatto, N. M., Thompson, A., Bordelon, Y. & Ritz, B. Occurrence of depression and anxiety prior to Parkinson’s disease. Parkinsonism Relat Disord 16, 576–581 (2010).
3. Walker, F. O. Huntington’s disease. Lancet 27, 143–150 (2007).
4. Roos, R. A. Huntington’s disease: a clinical review. Orphanet J Rare Dis 5, 40 (2010).
5. McColgan, P. & Tabrizi, S. J. Huntington’s disease: a clinical review. European Journal of Neurology vol. 25 24–34 Preprint at https://doi.org/10.1111/ene.13413 (2018).
6. Manoharan, S. et al. The Role of Reactive Oxygen Species in the Pathogenesis of Alzheimer’s Disease, Parkinson’s Disease, and Huntington’s Disease: A Mini Review. Oxidative Medicine and Cellular Longevity Preprint at https://doi.org/10.1155/2016/8590578 (2016).
7. Mortada, I. et al. Immunotherapies for Neurodegenerative Diseases. Frontiers in Neurology vol. 12 Preprint at https://doi.org/10.3389/fneur.2021.654739 (2021).
8. Durães, F., Pinto, M. & Sousa, E. Old drugs as new treatments for neurodegenerative diseases. Pharmaceuticals vol. 11 Preprint at https://doi.org/10.3390/ph11020044 (2018).
9. Li, X., Frye, M. A. & Shelton, R. C. Review of pharmacological treatment in mood disorders and future directions for drug development. Neuropsychopharmacology vol. 37 77–101 Preprint at https://doi.org/10.1038/npp.2011.198 (2012).
10. Scatena, R. et al. An update on pharmacological approaches to neurodegenerative disease. Expert Opinion on Investigational Drugs vol. 16 59–72 Preprint at https://doi.org/10.1517/13543784.16.1.59 (2007).
11. Castellano-Tejedor, C. Non-Pharmacological Interventions for the Management of Chronic Health Conditions and Non-Communicable Diseases. International Journal of Environmental Research and Public Health vol. 19 Preprint at https://doi.org/10.3390/ijerph19148536 (2022).
12. Scheller, E. L. & Krebsbach, P. H. Gene therapy: Design and prospects for craniofacial regeneration. Journal of Dental Research vol. 88 585–596 Preprint at https://doi.org/10.1177/0022034509337480 (2009).
13. Quinn, L. et al. Clinical recommendations to guide physical therapy practice for Huntington disease. Neurology vol. 94 217–228 Preprint at https://doi.org/10.1212/WNL.0000000000008887 (2020).
14. Quinn, L. et al. Physical activity and exercise outcomes in Huntington’s disease (PACE-HD): results of a 12-month trial-within-cohort feasibility study of a physical activity intervention in people with Huntington’s disease. Parkinsonism Relat Disord 101, 75–89 (2022).
15. Mueller, S. M., Petersen, J. A. & Jung, H. H. Exercise in huntington’s disease: Current state and clinical significance. Tremor and Other Hyperkinetic Movements vol. 9 1–10 Preprint at https://doi.org/10.7916/tm9j-f874 (2019).
16. Kay, C. et al. A Comprehensive Haplotype-Targeting Strategy for Allele-Specific HTT Suppression in Huntington Disease. Am J Hum Genet 105, 1112–1125 (2019).
17. Bloch, J. et al. Neuroprotective gene therapy for Huntington’s disease, using polymer-encapsulated cells engineered to secrete human ciliary neurotrophic factor: Results of a phase I study. Hum Gene Ther 15, 968–975 (2004).
18. Fiszer, A., Ellison-Klimontowicz, M. E. & Krzyzosiak, W. J. Silencing of genes responsible for polyQ diseases using chemically modified single-stranded siRNAs. Acta Biochim Pol 63, 759–764 (2016).
19. Pfister, E. L. et al. Five siRNAs Targeting Three SNPs May Provide Therapy for Three-Quarters of Huntington’s Disease Patients. Current Biology 19, 774–778 (2009).
20. 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).
21. Yu, D. et al. Single-stranded RNAs use RNAi to potently and allele-selectively inhibit mutant huntingtin expression. Cell 150, 895–908 (2012).
22. Zhang, Y., Engelman, J. & Friedlander, R. M. Allele-specific silencing of mutant Huntington’s disease gene. J Neurochem 108, 82–90 (2009).
23. Xu, X. et al. Reversal of Phenotypic Abnormalities by CRISPR/Cas9-Mediated Gene Correction in Huntington Disease Patient-Derived Induced Pluripotent Stem Cells. Stem Cell Reports 8, 619–633 (2017).
24. Kordasiewicz, H. B. et al. Sustained Therapeutic Reversal of Huntington’s Disease by Transient Repression of Huntingtin Synthesis. Neuron 74, 1031–1044 (2012).
25. Sathasivam, K. et al. Aberrant splicing of HTT generates the pathogenic exon 1 protein in Huntington disease. Proc Natl Acad Sci U S A 110, 2366–2370 (2013).
26. Boudreau, R. L. et al. Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington’s disease mice. Molecular Therapy 17, 1053–1063 (2009).
27. Cho, I. K., Hunter, C. E., Ye, S., Pongos, A. L. & Chan, A. W. S. Combination of stem cell and gene therapy ameliorates symptoms in Huntington’s disease mice. NPJ Regen Med 4, (2019).
28. Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 102, 5820–5825 (2005).
29. Ekman, F. K. et al. CRISPR-Cas9-Mediated Genome Editing Increases Lifespan and Improves Motor Deficits in a Huntington’s Disease Mouse Model. Mol Ther Nucleic Acids 17, 829–839 (2019).
30. Dey, N. D. et al. Genetically engineered mesenchymal stem cells reduce behavioral deficits in the YAC 128 mouse model of Huntington’s disease. Behavioural Brain Research 214, 193–200 (2010).
31. Pollock, K. et al. Human mesenchymal stem cells genetically engineered to overexpress brain-derived neurotrophic factor improve outcomes in huntington’s disease mouse models. Molecular Therapy 24, 965–977 (2016).
32. Difiglia, M. et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. PNAS 104, 17204–17209 (2007).
33. Agustín-Pavón, C., Mielcarek, M., Garriga-Canut, M. & Isalan, M. Deimmunization for gene therapy: Host matching of synthetic zinc finger constructs enables long-term mutant Huntingtin repression in mice. Mol Neurodegener 11, (2016).
34. Zeitler, B. et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat Med 25, 1131–1142 (2019).
35. Frank, S. Tetrabenazine as anti-chorea therapy in Huntington Disease: An open-label continuation study. Huntington Study Group/TETRA-HD Investigators. BMC Neurol 9, (2009).
36. Beglinger, L. J. et al. Randomized controlled trial of atomoxetine for cognitive dysfunction in early huntington disease. J Clin Psychopharmacol 29, 484–487 (2009).
37. Garcia de Yebenes, J. et al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 10, 1049–1057 (2011).
38. Ferrante, R. J. et al. Therapeutic Effects of Coenzyme Q 10 and Remacemide in Transgenic Mouse Models of Huntington’s Disease. Journal of Neuroscience 22, 15922–15999 (2002).
39. Zinzi, P. et al. Effects of an intensive rehabilitation programme on patients with Huntington’s disease: A pilot study. Clin Rehabil 21, 603–613 (2007).
40. Busse, M. et al. Q12 A randomised feasibility study of a 12-week exercise programme in Huntington’s disease (HD). J Neurol Neurosurg Psychiatry 83, A58.2-A59 (2012).
41. Kloos, A. D., Kegelmeyer, D. A., White, S. E. & Kostyk, S. K. The impact of different types of assistive devices on gait measures and safety in Huntington’s disease. PLoS One 7, (2012).
42. Kloos, A. D., Fritz, N. E., Kostyk, S. K., Young, G. S. & Kegelmeyer, D. A. Video game play (Dance Dance Revolution) as a potential exercise therapy in Huntington’s disease: A controlled clinical trial. Clin Rehabil 27, 972–982 (2013).
43. Piira, A. et al. Effects of a One Year Intensive Multidisciplinary Rehabilitation Program for Patients with Huntington’s Disease: A Prospective Intervention Study. PLoS Curr (2013) doi:10.1371/ currents.hd.9504af71e0d1f87830c25c394be47027
44. Piira, A. et al. Effects of a Two-Year Intensive Multidisciplinary Rehabilitation Program for Patients with Huntington’s Disease: a Prospective Intervention Study. PLoS Curr (2014) doi:10.1371 /currents.hd.2c56ceef7f9f8e239a59ecf2d94cddac.
45. Thompson, J. A. et al. The effects of multidisciplinary rehabilitation in patients with early-to-middle-stage Huntington’s disease: A pilot study. Eur J Neurol 20, 1325–1329 (2013).
46. Quinn, L. et al. Task-Specific Training in Huntington Disease: A Randomized Controlled Feasibility Trial. Physical Therapy Journal 94, 1555–1568 (2014).
47. Quinn, L. et al. A randomized, controlled trial of a multi-modal exercise intervention in Huntington’s disease. Parkinsonism Relat Disord 31, 46–52 (2016).
48. Quinn, L. et al. Physical activity and exercise outcomes in Huntington’s disease (PACE-HD): results of a 12-month trial-within-cohort feasibility study of a physical activity intervention in people with Huntington’s disease. Parkinsonism Relat Disord 101, 75–89 (2022).
49. Dawes, H. et al. Exercise testing and training in people with Huntington’s disease. Clin Rehabil 29, 196–206 (2015).
50. Khalil, H. et al. Adherence to use of a home-based exercise DVD in people with Huntington disease: Participants’ perspectives. Phys Ther 92, 69–82 (2012).
51. Cruickshank, T. M. et al. The effect of multidisciplinary rehabilitation on brain structure and cognition in Huntington’s disease: An exploratory study. Brain Behav 5, 1–10 (2015).
52. Cruickshank, T. M. et al. Effects of multidisciplinary therapy on physical function in Huntington’s disease. Acta Neurol Scand 138, 500–507 (2018).
53. 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).
54. Goold, R. et al. FAN1 modifies Huntington’s disease progression by stabilizing the expanded HTT CAG repeat. Hum Mol Genet 28, 650–661 (2019).
55. Kay, C. et al. The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 177, 346–357 (2018).
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