Summary
The ultimate goal for Huntington’s disease (HD) therapeutics is to develop disease-modifying neuroprotective therapies that can delay or prevent illness in those who are at genetic risk and can slow progression in those who are affected clinically. Neuroprotection is the preservation of neuronal structure, function, and viability, and neuroprotective therapy is thus targeted at the underlying pathology of HD, rather than at its specific symptoms. Preclinical target discovery research in HD is identifying numerous distinct targets, along with options for modulating them, with some proceeding into large-scale efficacy studies in early symptomatic HD subjects. The first pilot studies of neuroprotective compounds in premanifest HD are also soon to begin. This review discusses the opportunities for neuroprotection in HD, clinical methodology in premanifest and manifest HD, the clinical assessment of neuroprotection, molecular targets and therapeutic leads, and the current state of clinical development.
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Zhang X, Smith DL, Meriin AB, et al. A potent small molecule inhibits polyglutamine aggregation in Huntington’s disease neurons and suppresses neurodegeneration in vivo. Proc Natl Acad Sci U S A 2005;102: 892–897.
Chopra V, Fox JH, Lieberman G, et al. A small-molecule therapeutic lead for Huntington’s disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc Natl Acad Sci U S A 2007;104: 16685–16689.
Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington’s disease mutation: the sensitivity and specificity of measuring CAG repeats. N Engl J Med 1994;330: 1401–1406.
Myers RH, MacDonald ME, Koroshetz WJ, et al. De novo expansion of a (CAG)n repeat in sporadic Huntington’s disease. Nat Genet 1993;5: 168–173.
Goldberg YP, Kremer B, Andrew SE, et al. Molecular analysis of new mutations for Huntington’s disease: intermediate alleles and sex of origin effects. Nat Genet 1993;5: 174–179.
Dubinsky RM. No going home for hospitalized Huntington’s disease patients. Mov Disord 2005;20: 1316–1322.
Bonelli RM, Wenning GK. Pharmacological management of Huntington’s disease: an evidence-based review. Curr Pharm Des 2006;12: 2701–2720.
Bonelli RM, Hofmann P. A systematic review of the treatment studies in Huntington’s disease since 1990. Expert Opin Pharmacother 2007;8: 141–153.
Hersch SM, Ferrante RJ. Translating therapies for Huntington’s disease from genetic animal models to clinical trials. NeuroRx 2004;1: 298–306.
Beal MF, Ferrante RJ. Experimental therapeutics in transgenic mouse models of Huntington’ s disease. Nat Rev Neurosci 2004; 5: 373–384.
Hersch S, Greenamyre J. Huntington’s Disease. In: Johnson R, Griffin J, editors. Current therapy in neurologic disease. 5th ed. St. Louis: Mosby-Year Book, 1997. p. 275–279.
Anderson KE, Marder KS. An overview of psychiatric symptoms in Huntington’s disease. Curr Psychiatry Rep 2001;3: 379–388.
Rosenblatt A, Ranen NG, Nance M, Paulsen J. A physician’s guide to the management of Huntington’s Disease. 2nd ed. New York: Huntington’s Disease Society of America, 1999.
Simpson SA. Late stage care in Huntington’s disease. Brain Res Bull 2007;72: 179–181.
Vamos M, Hambridge J, Edwards M, Conaghan J. The impact of Huntington’s disease on family life. Psychosomatics 2007;48: 400–404.
Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72: 971–983.
Ferrante RJ, Kowall NW, Richardson EP Jr. Proliferative and degenerative changes in striatal spiny neurons in Huntington’s disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry. J Neurosci 1991;11: 3877–3887.
Sorrel A, Williams RS, Kaufmann WE, Myers RH. Evidence for neuronal degeneration and dendritic plasticity in cortical pyramidal neurons of Huntington’ s disease: a quantitative Golgi study. Neurology 1993;43: 2088–2096.
Hersch S, Ferrante R. Neuropathology and pathophysiology of Huntington’s disease. In: Watts R, Koller W, editors. Movement disorders: neurologic principles and practice. 1st ed. New York: McGraw-Hill, 1997: 503–526.
Rosas HD, Liu AK, Hersch S, et al. Regional and progressive thinning of the cortical ribbon in Huntington’s disease. Neurology 2002;58: 695–701.
Rosas HD, Hevelone ND, Zaleta AK, Greve DN, Salat DH, Fischl B. Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology 2005;65: 745–747.
Aylward EH, Codori AM, Barta PE, Pearlson GD, Harris GJ, Brandt J. Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. Arch Neurol 1996;53: 1293–1296.
Aylward EH, Codori AM, Rosenblatt A, et al. Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington’s disease. Mov Disord 2000;15: 552–560.
Borovecki F, Lovrecic L, Zhou J, et al. Genome-wide expression profiling of human blood reveals biomarkers for Huntington’s disease. Proc Natl Acad Sci U S A 2005;102: 11023–11028.
Gómez-Tortosa E, MacDonald ME, Friend JC, et al. Quantitative neuropathological changes in presymptomatic Huntington’s disease. Ann Neurol 2001;49: 29–34.
Paulsen JS, Zimbelman JL, Hinton SC, et al. fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington’s disease. AJNR Am J Neuroradiol 2004;25: 1715–1721.
Reading SA, Dziorny AC, Peroutka LA, et al. Functional brain changes in presymptomatic Huntington’s disease. Ann Neurol 2004;55: 879–883.
Rosas HD, Tuch DS, Hevelone ND, et al. Diffusion tensor imaging in presymptomatic and early Huntington’s disease: selective white matter pathology and its relationship to clinical measures. Mov Disord 2006;21: 1317–1325.
Huntington Study Group PHAROS Investigators. At risk for Huntington disease: the PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled. Arch Neurol 2006;63: 991–996.
Aylward EH. Change in MRI striatal volumes as a biomarker in preclinical Huntington’s disease. Brain Res Bull 2007;72: 152–158.
Julien CL, Thompson JC, Wild S, et al. Psychiatric disorders in preclinical Huntington’s disease. J Neurol Neurosurg Psychiatry 2007;78: 939–943.
Marshall J, White K, Weaver M, et al. Specific psychiatric manifestations among preclinical Huntington disease mutation carriers. Arch Neurol 2007;64: 116–121.
Duff K, Paulsen JS, Beglinger LJ, Langbehn DR, Stout JC; Predict-HD Investigators of the Huntington Study Group. Psychiatric symptoms in Huntington’s disease before diagnosis: the Predict-HD Study. Biol Psychiatry 2007;62: 1341–1346.
Klepac N, Relja M, Klepac R, Hećimović S, Babić T, Trkulja V. Oxidative stress parameters in plasma of Huntington’s disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects: a cross-sectional study. J Neurol 2007;254: 1676–1683.
Saft C, Zange J, Andrich J, et al. Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington’s disease. Mov Disord 2005;20: 674–679.
Varani K, Abbracchio MP, Cannella M, et al. Aberrant A2A receptor function in peripheral blood cells in Huntington’s disease. FASEB J 2003;17: 2148–2150.
Paulsen JS, Hayden M, Stout JC, et al.; Predict-HD Investigators of the Huntington Study Group. Preparing for preventive clinical trials: the Predict-HD study. Arch Neurol 2006;63: 883–890.
Langbehn DR, Brinkman RR, Falush D, Paulsen JS, Hayden MR. A new model for prediction of the age of onset and penetrance for Huntington’s disease based on CAG length. Clin Genet 2004;65: 267–277.
Langbehn DR, Paulsen JS. Predictors of diagnosis in Huntington disease. Neurology 2007;68: 1710–1717.
Tibben A, Niermeijer MF, Roos RA, et al. Understanding the low uptake of presymptomatic DNA testing for Huntington’s disease. Lancet 1992;340: 1416.
Penziner E, Williams JK, Erwin C, et al. Perceptions of discrimination among persons who have undergone predictive testing for Huntington’s disease. Am J Med Genet B Neuropsychiatr Genet 2007 Oct 19 [Epub ahead of print].
Lilani A. Ethical issues and policy analysis for genetic testing: Huntington’s disease as a paradigm for diseases with a late onset. Hum Reprod Genet Ethics 2005;11: 28–34.
Robins Wahlin TB. To know or not to know: a review of behaviour and suicidal ideation in preclinical Huntington’s disease. Patient Educ Couns 2007;65: 279–287.
Timman R, Roos R, Maat-Kievit A, Tibben A. Adverse effects of predictive testing for Huntington disease underestimated: long-term effects 7–10 years after the test. Health Psychol 2004;23: 189–197.
Marder K, Zhao H, Myers RH, et al.; Huntington Study Group. Rate of functional decline in Huntington’s disease [Erratum in: Neurology 2000;54:1712]. Neurology 2000;54: 452–458.
NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology 2006;66: 664–671.
Witjes-Ané MN, Mertens B, van Vugt JP, Bachoud-Lévi AC, van Ommen GJ, Roos RA. Longitudinal evaluation of “presymptomatic” carriers of Huntington’s disease. J Neuropsychiatry Clin Neurosci 2007;19: 310–317.
DiFiglia M, Sapp E, Chase K, et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 1995;14: 1075–1081.
Gutekunst CA, Li SH, Yi H, Ferrante RJ, Li XJ, Hersch SM. The cellular and subcellular localization of huntingtin-associated protein 1 (HAP1): comparison with huntingtin in rat and human. J Neurosci 1998;18: 7674–7686.
Persichetti F, Ambrose CM, Ge P, et al. Normal and expanded Huntington’s disease gene alleles produce distinguishable proteins due to translation across the CAG repeat. Mol Med 1995; 1: 374–383.
Sharp AH, Loev SJ, Schilling G, et al. Widespread expression of Huntington’s disease gene (IT15) protein product. Neuron 1995; 14: 1065–1074.
Trottier Y, Devys D, Imbert G, et al. Cellular localization of the Huntington’s disease protein and discrimination of the normal and mutated form. Nat Genet 1995;10: 104–110.
Cattaneo E, Rigamonti D, Goffredo D, Zuccato C, Squitieri F, Sipione S. Loss of normal huntingtin function: new developments in Huntington’s disease research. Trends Neurosci 2001;24: 182–188.
Cattaneo E, Zuccato C, Tartari M. Normal huntingtin function: an alternative approach to Huntington’s disease. Nat Rev Neurosci 2005;6: 919–930.
Zuccato C, Ciammola A, Rigamonti D, et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington’s disease. Science 2001;293: 493–498.
Goldberg YP, Nicholson DW, Rasper DM, et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 1996;13: 442–449.
Wellington CL, Brinkman RR, O’Kusky JR, Hayden MR. Toward understanding the molecular pathology of Huntington’s disease. Brain Pathol 1997;7: 979–1002.
Wellington CL, Ellerby LM, Gutekunst CA, et al. Caspase cleavage of mutant huntingtin precedes neurodegeneration in Huntington’s disease. J Neurosci 2002;22: 7862–7872.
Hoffner G, Island ML, 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 2005;95: 125–136.
Graham RK, Deng Y, Slow EJ, et al. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell 2006;125: 1179–1191.
Kaltenbach LS, Romero E, Becklin RR, et al. Huntingtin interacting proteins are genetic modifiers of neurodegeneration. PLoS Genet 2007;3: e82.
Smith KM, Matson S, Matson WR, et al. Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington’s disease mice. Biochim Biophys Acta 2006;1762: 616–626.
McGill JK, Beal MF. PGC-1α, a new therapeutic target in Huntington’s disease? Cell 2006;127: 465–468.
Ryu H, Rosas HD, Hersch SM, Ferrante RJ. The therapeutic role of creatine in Huntington’s disease. Pharmacol Ther 2005;108: 193–207.
Browne SE, Beal MF. Oxidative damage in Huntington’s disease pathogenesis. Antioxid Redox Signal 2006;8: 2061–2073.
Altmann SM, Muryshev A, Fossale E, et al. Discovery of bioactive small-molecule inhibitor of poly ADP-ribose polymerase: implications for energy-deficient cells. Chem Biol 2006;13: 765–770.
Kovtun IV, Liu Y, Bjoras M, Klungland A, Wilson SH, McMurray CT. OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells. Nature 2007;447: 447–452.
Stack EC, Dedeoglu A, Smith KM, et al. Neuroprotective effects of synaptic modulation in Huntington’s disease R6/2 mice. J Neurosci 2007;27: 12908–12915.
Cepeda C, Hurst RS, Calvert CR, et al. Transient and progressive electrophysiological alterations in the corticostriatal pathway in a mouse model of Huntington’s disease. J Neurosci 2003;23: 961–969.
Pattison LR, Kotter MR, Fraga D, Bonelli RM. Apoptotic cascades as possible targets for inhibiting cell death in Huntington’ s disease. J Neurol 2006;253: 1137–1142.
Davies SW, Turmaine M, Cozens BA, et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 1997;90: 537–548.
DiFiglia M, Sapp E, Chase KO, et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 1997;277: 1990–1993.
Gutekunst CA, Li SH, Yi H, et al. Nuclear and neuropil aggregates in Huntington’s disease: relationship to neuropathology. J Neurosci 1999;19: 2522–2534.
Jana NR, Zemskov EA, Wang G, Nukina N. Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. Hum Mol Genet 2001;10: 1049–1059.
Sarkar S, Perlstein EO, Imarisio S, et al. Small molecules enhance autophagy and reduce toxicity in Huntington’s disease models. Nat Chem Biol 2007;3: 331–338.
Ventruti A, Cuervo AM. Autophagy and neurodegeneration. Curr Neurol Neurosci Rep 2007;7: 443–451.
Floto RA, Sarkar S, Perlstein EO, Kampmann B, Schreiber SL, Rubinsztein DC. Small molecule enhancers of rapamycin-induced TOR inhibition promote autophagy, reduce toxicity in Huntington’s disease models and enhance killing of mycobacteria by macrophages. Autophagy 2007;3: 620–622.
Yamamoto A, Cremona ML, Rothman JE. Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway. J Cell Biol 2006;172: 719–731.
Ravikumar B, Rubinsztein DC. Role of autophagy in the clearance of mutant huntingtin: a step towards therapy? Mol Aspects Med 2006;27: 520–527.
Seo H, Sonntag KC, Kim W, Cattaneo E, Isacson O. Proteasome activator enhances survival of Huntington’s disease neuronal model cells. PLoS ONE 2007;2: e238.
Bennett EJ, Shaler TA, Woodman B, et al. Global changes to the ubiquitin system in Huntington’s disease. Nature 2007;448: 704–708.
Howard RA, Sharma P, Hajjar C, et al. Ubiquitin conjugating enzymes participate in polyglutamine protein aggregation. BMC Cell Biol 2007;8: 32.
Zuccato C, Belyaev N, Conforti P, et al. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease. J Neurosci 2007;27: 6972–6983.
Strand AD, Baquet ZC, Aragaki AK, et al. Expression profiling of Huntington’s disease models suggests that brain-derived neurotrophic factor depletion plays a major role in striatal degeneration. J Neurosci 2007;27: 11758–11768.
Zuccato C, Liber D, Ramos C, et al. Progressive loss of BDNF in a mouse model of Huntington’s disease and rescue by BDNF delivery. Pharmacol Res 2005;52: 133–139.
Dompierre JP, Godin JD, Charrin BC, et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci 2007;27: 3571–3583.
Hersch SM. Huntington’s disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation. Curr Opin Neurol 2003;16: 501–506.
Yang W, Dunlap JR, Andrews RB, Wetzel R. Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. Hum Mol Genet 2002;11: 2905–2917.
Schilling G, Savonenko AV, Klevytska A, et al. Nuclear-targeting of mutant huntingtin fragments produces Huntington’s disease-like phenotypes in transgenic mice. Hum Mol Genet 2004;13: 1599–1610.
Boutell JM, Thomas P, Neal JW, et al. Aberrant interactions of transcriptional repressor proteins with the Huntington’s disease gene product, huntingtin. Hum Mol Genet 1999;8: 1647–1655.
Dunah AW, Jeong H, Griffin A, et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington’ s disease. Science 2002;296: 2238–2243.
Holbert S, Denghien I, Kiechle T, et al. The Gln-A1a repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington’s disease pathogenesis. Proc Natl Acad Sci U S A 2001;98: 1811–1816.
Nucifora FC Jr, Sasaki M, Peters MF, et al. Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science 2001;291: 2423–2428.
Steffan JS, Bodai L, Pallos J, et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 2001;413: 739–743.
Steffan JS, Kazantsev A, Spasic-Boskovic O, et al. The Huntington’s disease protein interacts with p53 and CREB-binding protein and represses transcription. Proc Natl Acad Sci U S A 2000; 97: 6763–6768.
McCampbell A, Taylor JP, Taye AA, et al. CREB-binding protein sequestration by expanded polyglutamine. Hum Mol Genet 2000; 9: 2197–2202.
Sadri-Vakili G, Bouzou B, Benn CL, et al. Histones associated with downregulated genes are hypo-acetylated in Huntington’s disease models. Hum Mol Genet 2007;16: 1293–1306.
Stack EC, Del Signore SJ, Luthi-Carter R, et al. Modulation of nucleosome dynamics in Huntington’s disease. Hum Mol Genet 2007;16: 1164–1175.
Kazantsev AG, Hersch SM. Drug targeting of dysregulated transcription in Huntington’s disease. Prog Neurobiol 2007;83: 249–259.
Sadri-Vakili G, Cha JH. Mechanisms of disease: histone modifications in Huntington’s disease. Nat Clin Pract Neurol 2006;2: 330–338.
Butler R, Bates GP. Histone deacetylase inhibitors as therapeutics for polyglutamine disorders. Nat Rev Neurosci 2006;7: 784–796.
DiFiglia M, Sena-Esteves M, Chase K, et al. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A 2007;104: 17204–17209.
Denovan-Wright EM, Davidson BL. RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases. Gene Ther 2006;13: 525–531.
Miller TW, Messer A. Intrabody applications in neurological disorders: progress and future prospects. Mol Ther 2005;12: 394–401.
Coufal M, Maxwell MM, Russel DE, et al. Discovery of a novel small-molecule targeting selective clearance of mutant huntingtin fragments. J Biomol Screen 2007;12: 351–360.
Valera AG, Diaz-Hernandez M, Hernandez F, Ortega Z, Lucas JJ. The ubiquitin-proteasome system in Huntington’s disease. Neuroscientist 2005; 11: 583–594.
Brignull HR, Morley JF, Morimoto RI. The stress of misfolded proteins: C. elegans models for neurodegenerative disease and aging. Adv Exp Med Biol 2007;594: 167–189.
Ferrante RJ, Andreassen OA, Dedeoglu A, et al. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington’s disease. J Neurosci 2002;22: 1592–1599.
Andreassen OA, Dedeoglu A, Ferrante RJ, et al. Creatine increases survival and delays motor symptoms in a transgenic animal model of Huntington’s disease. Neurobiol Dis 2001;8: 479–491.
Ferrante RJ, Andreassen OA, Jenkins BG, et al. Neuroprotective effects of creatine in a transgenic mouse model of Huntington’s disease. J Neurosci 2000;20: 4389–4397.
Andreassen OA, Ferrante RJ, Huang HM, et al. Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington’s disease. Ann Neurol 2001;50: 112–117.
Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF. Lipoic acid improves survival in transgenic mouse models of Huntington’s disease. Neuroreport 2001;12: 3371–3373.
Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 2000;6: 797–801.
Dedeoglu A, Kubilus JK, Jeitner TM, et al. Therapeutic effects of cystamine in a murine model of Huntington’s disease. J Neurosci 2002;22: 8942–8950.
Karpuj MV, Garren H, Slunt H, et al. Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington’s disease brain nuclei. Proc Natl Acad Sci U S A 1999;96: 7388–7393.
Nguyen T, Hamby A, Massa SM. Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington’s disease mouse model. Proc Natl Acad Sci U S A 2005;102: 11840–11845.
Youdim MB, Stephenson G, Ben Shachar D. Ironing iron out in Parkinson’s disease and other neurodegenerative diseases with iron chelators: a lesson from 6-hydroxydopamine and iron chelators, desferal and VK-28. Ann N Y Acad Sci 2004;1012: 306–325.
Landwehrmeyer GB, Dubois B, de Yebenes JG, et al. Riluzole in Huntington’s disease: a 3-year, randomized controlled study. Ann Neurol 2007;62: 262–272.
Rosas HD, Koroshetz WJ, Jenkins BG, et al. Riluzole therapy in Huntington’s disease (HD). Mov Disord 1999;14: 326–330.
Duan W, Guo Z, Jiang H, et al. Paroxetine retards disease onset and progression in Huntingtin mutant mice. Ann Neurol 2004; 55: 590–594.
Hockly E, Richon VM, Woodman B, et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington’s disease. Proc Natl Acad Sci U S A 2003;100: 2041–2046.
Ferrante RJ, Kubilus JK, Lee J, et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J Neurosci 2003;23: 9418–9427.
Ferrante RJ, Ryu H, Kubilus JK, et al. Chemotherapy for the brain: the antitumor antibiotic mithramycin prolongs survival in a mouse model of Huntington’s disease. J Neurosci 2004;24: 10335–10342.
Gardian G, Browne SE, Choi DK, et al. Neuroprotective effects of phenylbutyrate in the N171-82Q transgenic mouse model of Huntington’s disease. J Biol Chem 2005;280: 556–563.
Keene CD, Rodrigues CM, Eich T, Chhabra MS, Steer CJ, Low WC. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. Proc Natl Acad Sci U S A 2002;99: 10671–10676.
Zuccato C, Cattaneo E. Role of brain-derived neurotrophic factor in Huntington’s disease. Prog Neurobiol 2007;81: 294–330.
Ranen NG, Peyser CE, Coyle JT, et al. A controlled trial of idebenone in Huntington’s disease. Mov Disord 1996;11: 549–554.
Peyser CE, Folstein M, Chase GA, et al. Trial of d-alpha-tocopherol in Huntington’s disease. Am J Psychiatry 1995;152: 1771–1775.
Huntington Study Group. Safety and tolerability of the free-radical scavenger OPC-14117 in Huntington’s disease. Neurology 1998;50: 1366–1373.
Tabrizi SJ, Blamire AM, Manners DN, et al. High-dose creatine therapy for Huntington disease: a 2-year clinical and MRS study. Neurology 2005;64: 1655–1656.
Hersch SM, Gevorkian S, Marder K, et al. Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG. Neurology 2006;66: 250–252.
Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease. Neurology 2001;57: 397–404.
Dubinsky R, Gray C. CYTE-I-HD: phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington’s disease. Mov Disord 2006;21: 530–533.
Puri BK, Leavitt BR, Hayden MR, et al. Ethyl-EPA in Huntington disease: a double-blind, randomized, placebo-controlled trial. Neurology 2005;65: 286–292.
Kremer B, Clark C, Hardy M, Almqvist E, Raymond L, Hayden M. Lamotrigine does not retard the progression of Huntington’s disease. WFN Working Group on Huntington’s Disease 1997:34.
Huntington Study Group. Dosage effects of riluzole in Huntington’s disease: a multicenter placebo-controlled study. Neurology 2003;61: 1551–1556.
Seppi K, Mueller J, Bodner T, et al. Riluzole in Huntington’s disease (HD): an open label study with one year follow up. J Neurol 2001;248: 866–869.
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Hersch, S.M., Rosas, H.D. Neuroprotection for Huntington’s disease: Ready, set, slow. Neurotherapeutics 5, 226–236 (2008). https://doi.org/10.1016/j.nurt.2008.01.003
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DOI: https://doi.org/10.1016/j.nurt.2008.01.003