New Avenues for the Treatment of Huntington’s Disease

Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.

References 437

1. 1.

   Brinkman R.R., Mezei M.M., Theilmann J., Almqvist E., Hayden M.R. The likelihood of being affected with huntington disease by a particular age, for a specific CAG size. Am. J. Hum. Genet. 1997;60:1202-1210.

   Not in our library

2. 2.
   Huntington's disease: a clinical review · 2010

   No notice
3. 3.

   Galts C.P.C., Bettio L.E.B., Jewett D.C., Yang C.C., Brocardo P.S., Rodrigues A.L.S., Thacker J.S., Gil-Mohapel J. Depression in neurodegenerative diseases: Common mechanisms and current treatment options. Neurosci. Biobehav. Rev. 2019;102:56-84.

   Not in our library10.1016/j.neubiorev.2019.04.002

4. 4.

   Dorsey E.R., Beck C.A., Darwin K., Nichols P., Brocht A.F.D., Biglan K.M., Shoulson I. Natural history of Huntington disease. JAMA Neurol. 2013;70:1520-1530.

   Not in our library10.1001/jamaneurol.2013.4408

5. 5.

   Lanska D.J., Lavine L., Lanska M.J., Schoenberg B.S. Huntington’s disease mortality in the United States. Neurology. 1988;38:769-772.

   Not in our library10.1212/wnl.38.5.769

6. 6.

   Lee J.M., Wheeler V.C., Chao M.J., Vonsattel J.P.G., Pinto R.M., Lucente D., Abu-Elneel K., Ramos E.M., Mysore J.S., Gillis T., et al. Identification of Genetic Factors that Modify Clinical Onset of Huntington’s Disease. Cell. 2015;162:516-526.

   Not in our library10.1016/j.cell.2015.07.003

7. 7.

   Pringsheim T., Wiltshire K., Day L., Dykeman J., Steeves T., Jette N. The incidence and prevalence of Huntington’s disease: A systematic review and meta-analysis. Mov. Disord. 2012;27:1083-1091.

   Not in our library10.1002/mds.25075

8. 8.

   Kay C., Collins J.A., Wright G.E.B., Baine F., Miedzybrodzka Z., Aminkeng F., Semaka A.J., McDonald C., Davidson M., Madore S.J., et al. The molecular epidemiology of Huntington disease is related to intermediate allele frequency and haplotype in the general population. Am. J. Med. Genet. Part B Neuropsychiatr. Genet. 2018;177:346-357.

   Not in our library10.1002/ajmg.b.32618

9. 9.

   Rawlins M.D., Wexler N.S., Wexler A.R., Tabrizi S.J., Douglas I., Evans S.J.W., Smeeth L. The Prevalence of Huntington’s Disease. Neuroepidemiology. 2016;46:144-153.

   Not in our library10.1159/000443738

10. 10.

    Fisher E.R., Hayden M.R. Multisource ascertainment of Huntington disease in Canada: Prevalence and population at risk. Mov. Disord. 2014;29:105-114.

    Not in our library10.1002/mds.25717

11. 11.

    MacDonald M.E., Ambrose C.M., Duyao M.P., Myers R.H., Lin C., Srinidhi L., Barnes G., Taylor S.A., James M., Groot N., et al. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993;72:971-983.

    Not in our library10.1016/0092-8674(93)90585-e

12. 12.

    Ochaba J., Lukacsovich T., Csikos G., Zheng S., Margulis J., Salazar L., Mao K., Lau A.L., Yeung S.Y., Humbert S., et al. Potential function for the Huntingtin protein as a scaffold for selective autophagy. Proc. Natl. Acad. Sci. USA. 2014;111:16889-16894.

    Not in our library10.1073/pnas.1420103111

13. 13.

    Liu J.P., Zeitlin S.O. Is huntingtin dispensable in the adult brain? J. Huntingtons. Dis. 2017;6:1-17.

    Not in our library10.3233/jhd-170235

14. 14.

    Dayalu P., Albin R.L. Huntington Disease. Neurol. Clin. 2015;33:101-114.

    Not in our library10.1016/j.ncl.2014.09.003

15. 15.

    Semaka A., Kay C., Doty C., Collins J.A., Bijlsma E.K., Richards F., Goldberg Y.P., Hayden M.R. CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J. Med. Genet. 2013;50:696-703.

    Not in our library10.1136/jmedgenet-2013-101796

16. 16.

    Aziz N.A., Jurgens C.K., Landwehrmeyer G.B., Van Roon-Mom W.M.C., Van Ommen G.J.B., Stijnen T., Roos R.A.C. Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. Neurology. 2009;73:1280-1285.

    Not in our library10.1212/wnl.0b013e3181bd1121

17. 17.

    Arning L., Kraus P.H., Valentin S., Saft C., Andrich J., Epplen J.T. NR2A and NR2B receptor gene variations modify age at onset in Huntington disease. Neurogenetics. 2005;6:25-28.

    Not in our library10.1007/s10048-004-0198-8

18. 18.

    Wexler N.S., Lorimer J., Porter J., Gomez F., Moskowitz C., Shackell E., Marder K., Penchaszadeh G., Roberts S.A., Gayan J., et al. Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington’s disease age of onset. Proc. Natl. Acad. Sci. USA. 2004;101:3498-3503.

    Not in our library10.1073/pnas.0308679101

19. 19.

    Rüb U., Seidel K., Heinsen H., Vonsattel J.P., den Dunnen W.F., Korf H.W. Huntington’s disease (HD): The neuropathology of a multisystem neurodegenerative disorder of the human brain. Brain Pathol. 2016;26:726-740.

    Not in our library10.1111/bpa.12426

20. 20.

    DiFiglia M., Sapp E., Chase K.O., Davies S.W., Bates G.P., Vonsattel J.P., Aronin N. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science. 1997;277:1990-1993.

    Not in our library10.1126/science.277.5334.1990

21. 21.

    Papoutsi M., Labuschagne I., Tabrizi S.J., Stout J.C. The cognitive burden in Huntington’s disease: Pathology, phenotype, and mechanisms of compensation. Mov. Disord. 2014;29:673-683.

    Not in our library10.1002/mds.25864

22. 22.

    Vonsattel J., Myers R.H., Stevens T.J., Ferrante R.J., Bird E.D., Richardson E.P. Neuropathological Classification of Huntington’s Disease. J. Neuropathol. Exp. Neurol. 1985;44:559-577.

    Not in our library10.1097/00005072-198511000-00003

23. 23.

    De La Monte S.M., Vonsattel J.P., Richardson E.P. Morphometric demonstration of atrophic changes in the ceRebral cortex, white matter, and neostriatum in huntington’s disease. J. Neuropathol. Exp. Neurol. 1988;47:516-525.

    Not in our library10.1097/00005072-198809000-00003

24. 24.

    Heinsen H., Rüb U., Bauer M., Ulmar G., Bethke B., Schüler M., Böcker F., Eisenmenger W., Götz M., Korr H., et al. Nerve cell loss in the thalamic mediodorsal nucleus in Huntington’s disease. Acta Neuropathol. 1999;97:613-622.

    Not in our library10.1007/s004010051037

25. 25.

    Rosas H.D., Liu A.K., Hersch S., Glessner M., Ferrante R.J., Salat D.H., Van Der Kouwe A., Jenkins B.G., Dale A.M., Fischl B. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology. 2002;58:695-701.

    Not in our library10.1212/wnl.58.5.695

26. 26.

    Peterseén Å., Gil J., Maat-Schieman M.L.C., Björkqvist M., Tanila H., Araújo I.M., Smith R., Popovic N., Wierup N., Norlén P., et al. Orexin loss in Huntington’s disease. Hum. Mol. Genet. 2005;14:39-47.

    Not in our library10.1093/hmg/ddi004

27. 27.

    Rüb U., Hoche F., Brunt E.R., Heinsen H., Seidel K., Del Turco D., Paulson H.L., Bohl J., Von Gall C., Vonsattel J.P., et al. Degeneration of the cerebellum in huntingtons disease (HD): Possible relevance for the clinical picture and potential gateway to pathological mechanisms of the disease process. Brain Pathol. 2013;23:165-177.

    Not in our library10.1111/j.1750-3639.2012.00629.x

28. 28.

    Rüb U., Hentschel M., Stratmann K., Brunt E., Heinsen H., Seidel K., Bouzrou M., Auburger G., Paulson H., Vonsattel J.-P., et al. Huntington’s Disease (HD): Degeneration of Select Nuclei, Widespread Occurrence of Neuronal Nuclear and Axonal Inclusions in the Brainstem. Brain Pathol. 2014;24:247-260.

    Not in our library10.1111/bpa.12115

29. 29.

    Cattaneo E., Zuccato C., Tartari M. Normal huntingtin function: An alternative approach to Huntington’s disease. Nat. Rev. Neurosci. 2005;6:919-930.

    Not in our library10.1038/nrn1806

30. 30.

    Gil J.M., Rego A.C. Mechanisms of neurodegeneration in Huntington’s disease. Eur. J. Neurosci. 2008;27:2803-2820.

    Not in our library10.1111/j.1460-9568.2008.06310.x

31. 31.

    Sturrock A., Leavitt B.R. The clinical and genetic features of Huntington disease. J. Geriatr. Psychiatry Neurol. 2010;23:243-259.

    Not in our library10.1177/0891988710383573

32. 32.

    Nance M.A. Huntington disease: Clinical, genetic, and social aspects. J. Geriatr. Psychiatry Neurol. 1998;11:61-70.

    Not in our library10.1177/089198879801100204

33. 33.

    Schiffmann S.N., Vanderhaeghen J.J. Adenosine A2 receptors regulate the gene expression of striatopallidal and striatonigral neurons. J. Neurosci. 1993;13:1080-1087.

    Not in our library10.1523/jneurosci.13-03-01080.1993

34. 34.

    André V.M., Cepeda C., Levine M.S. Dopamine and glutamate in huntington’s disease: A balancing act. CNS Neurosci. Ther. 2010;16:163-178.

    Not in our library10.1111/j.1755-5949.2010.00134.x

35. 35.

    Joel D. Open interconnected model of basal ganglia-thalamocortical circuitry and its relevance to the clinical syndrome of Huntington’s disease. Mov. Disord. 2001;16:407-423.

    Not in our library10.1002/mds.1096

36. 36.

    Nelson A.B., Kreitzer A.C. Reassessing Models of Basal Ganglia Function and Dysfunction. Annu. Rev. Neurosci. 2014;37:117-135.

    Not in our library10.1146/annurev-neuro-071013-013916

37. 37.

    Butters N., Wolfe J., Martone M., Granholm E., Cermak L.S. Memory disorders associated with huntington’s disease: Verbal recall, verbal recognition and procedural memory. Neuropsychologia. 1985;23:729-743.

    Not in our library10.1016/0028-3932(85)90080-6

38. 38.

    Pillons B., Dubois B., Agid Y. Severity and Specificity of Cognitive Impairment in Alzheimer’s, Huntington’s, and Parkinson’s Diseases and Progressive Supranuclear Palsy. Ann. N. Y. Acad. Sci. 1991;640:224-227.

    Not in our library10.1111/j.1749-6632.1991.tb00222.x

39. 39.

    Shiwach R. Psychopathology in Huntington’s disease patients. Acta Psychiatr. Scand. 1994;90:241-246.

    Not in our library10.1111/j.1600-0447.1994.tb01587.x

40. 40.

    Di Maio L., Squitieri F., Napolitano G., Campanella G., Trofatter J.A., Conneally P.M. Suicide risk in Huntington’s disease. J. Med. Genet. 1993;30:293-295.

    Not in our library10.1136/jmg.30.4.293

Cited by papers we hold 2

• The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets · 2024
  No notice
• Enriched Environment and Exercise Enhance Stem Cell Therapy for Stroke, Parkinson’s Disease, and Huntington’s Disease · 2022
  Not checked

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.