Neuroprotection for Huntington’s disease: Ready, set, slow

SummaryThe 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.

[1]  Safety and tolerability of the free-radical scavenger OPC-14117 in Huntington's disease , 1998, Neurology.

[2]  R. Dubinsky,et al.  CYTE‐I‐HD: Phase I dose finding and tolerability study of cysteamine (Cystagon) in Huntington's disease , 2006, Movement disorders : official journal of the Movement Disorder Society.

[3]  S. Hersch,et al.  The Cellular and Subcellular Localization of Huntingtin-Associated Protein 1 (HAP1): Comparison with Huntingtin in Rat and Human , 1998, The Journal of Neuroscience.

[4]  D. Rubinsztein,et al.  Role of autophagy in the clearance of mutant huntingtin: a step towards therapy? , 2006, Molecular aspects of medicine.

[5]  K. Marder,et al.  An overview of psychiatric symptoms in Huntington’s disease , 2001, Current psychiatry reports.

[6]  T. Babić,et al.  Oxidative stress parameters in plasma of Huntington's disease patients, asymptomatic Huntington’s disease gene carriers and healthy subjects , 2007, Journal of Neurology.

[7]  Christopher A Ross,et al.  Widespread expression of Huntington's disease gene (IT15) protein product , 1995, Neuron.

[8]  G. Ommen,et al.  Understanding the low uptake of presymptomatic DNA testing for Huntington's disease , 1992, The Lancet.

[9]  R H Myers,et al.  Quantitative neuropathological changes in presymptomatic Huntington's disease , 2001, Annals of neurology.

[10]  M. Beal,et al.  Neuroprotective Effects of Phenylbutyrate in the N171-82Q Transgenic Mouse Model of Huntington's Disease* , 2005, Journal of Biological Chemistry.

[11]  K. Varani,et al.  Aberrant A2A receptor function in peripheral blood cells in Huntington's disease , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[12]  S. Hersch,et al.  Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease , 2000, Nature Medicine.

[13]  G. Pearlson,et al.  Rate of caudate atrophy in presymptomatic and symptomatic stages of Huntington's disease , 2000, Movement disorders : official journal of the Movement Disorder Society.

[14]  S. Hersch,et al.  Drug targeting of dysregulated transcription in Huntington's disease , 2007, Progress in Neurobiology.

[15]  Howard Schulman,et al.  Global changes to the ubiquitin system in Huntington's disease , 2007, Nature.

[16]  Y. Kawaoka,et al.  Epidermal immunization by a needle-free powder delivery technology: Immunogenicity of influenza vaccine and protection in mice , 2000, Nature Medicine.

[17]  M. Beal,et al.  Experimental therapeutics in transgenic mouse models of Huntington's disease , 2004, Nature Reviews Neuroscience.

[18]  Leslie M Thompson,et al.  Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  S. Schreiber,et al.  Small molecules enhance autophagy and reduce toxicity in Huntington's disease models. , 2007, Nature chemical biology.

[20]  M. Hayden,et al.  The Gln-Ala repeat transcriptional activator CA150 interacts with huntingtin: neuropathologic and genetic evidence for a role in Huntington's disease pathogenesis. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Craufurd,et al.  Psychiatric disorders in preclinical Huntington’s disease , 2006, Journal of Neurology, Neurosurgery & Psychiatry.

[22]  Elena Cattaneo,et al.  Normal huntingtin function: an alternative approach to Huntington's disease , 2005, Nature Reviews Neuroscience.

[23]  Carlos Cepeda,et al.  Transient and Progressive Electrophysiological Alterations in the Corticostriatal Pathway in a Mouse Model of Huntington's Disease , 2003, The Journal of Neuroscience.

[24]  S. Folstein,et al.  Trial of d-α-tocopherol in Huntington's disease , 1995 .

[25]  T. B. Wahlin,et al.  To know or not to know: a review of behaviour and suicidal ideation in preclinical Huntington's disease. , 2007, Patient education and counseling.

[26]  R. Abagyan,et al.  Discovery of bioactive small-molecule inhibitor of poly adp-ribose polymerase: implications for energy-deficient cells. , 2006, Chemistry & biology.

[27]  G. Pearlson,et al.  Basal ganglia volume and proximity to onset in presymptomatic Huntington disease. , 1996, Archives of neurology.

[28]  J. M. Boutell,et al.  Aberrant interactions of transcriptional repressor proteins with the Huntington's disease gene product, huntingtin. , 1999, Human molecular genetics.

[29]  A. Lilani.  Ethical Issues and Policy Analysis for Genetic Testing: Huntington's Disease as a Paradigm for Diseases with a Late Onset , 2005, Human reproduction and genetic ethics.

[30]  R. Jolly.  The ubiquitin proteasome system in Huntington's disease , 2008 .

[31]  A. Dale,et al.  Regional and progressive thinning of the cortical ribbon in Huntington’s disease , 2002, Neurology.

[32]  M. MacDonald,et al.  Normal and Expanded Huntington’s Disease Gene Alleles Produce Distinguishable Proteins Due to Translation Across the CAG Repeat , 1995, Molecular medicine.

[33]  S. Simpson.  Late stage care in Huntington's disease , 2007, Brain Research Bulletin.

[34]  Elena Cattaneo,et al.  Progressive loss of BDNF in a mouse model of Huntington's disease and rescue by BDNF delivery. , 2005, Pharmacological research.

[35]  J. Palo,et al.  [Huntington's disease]. , 1986, Duodecim; laaketieteellinen aikakauskirja.

[36]  E. Siemers,et al.  Rate of functional decline in Huntington’s disease , 2000, Neurology.

[37]  A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington’s disease , 2001, Neurology.

[38]  S. Hersch,et al.  Neuroprotective Effects of Synaptic Modulation in Huntington's Disease R6/2 Mice , 2007, The Journal of Neuroscience.

[39]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[40]  R. Bonelli,et al.  Pharmacological management of Huntington's disease: an evidence-based review. , 2006, Current pharmaceutical design.

[41]  X. Beristain,et al.  Specific psychiatric manifestations among preclinical Huntington disease mutation carriers. , 2007, Archives of neurology.

[42]  D. Housman,et al.  The Huntington's disease protein interacts with p53 and CREB-binding protein and represses transcription. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[43]  A. Hamby,et al.  Clioquinol down-regulates mutant huntingtin expression in vitro and mitigates pathology in a Huntington's disease mouse model. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[44]  A. Young,et al.  A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivo. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[45]  Steven M. Hersch,et al.  Translating therapies for Huntington’s disease from genetic animal models to clinical trials , 2004 .

[46]  B. Landwehrmeyer,et al.  Mitochondrial impairment in patients and asymptomatic mutation carriers of Huntington's disease , 2005, Movement disorders : official journal of the Movement Disorder Society.

[47]  A. Falek,et al.  Huntington's Disease , 2008 .

[48]  W. Poewe,et al.  Riluzole in Huntington's disease (HD): an open label study with one year follow up , 2001, Journal of Neurology.

[49]  O. Andreassen,et al.  Creatine Increases Survival and Delays Motor Symptoms in a Transgenic Animal Model of Huntington's Disease , 2001, Neurobiology of Disease.

[50]  R V Jensen,et al.  Genome-wide expression profiling of human blood reveals biomarkers for Huntington's disease. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[51]  Jane S. Paulsen,et al.  fMRI biomarker of early neuronal dysfunction in presymptomatic Huntington's Disease. , 2004, AJNR. American journal of neuroradiology.

[52]  D. Price,et al.  Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[53]  Jane S. Paulsen,et al.  Perceptions of discrimination among persons who have undergone predictive testing for Huntington's disease , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[54]  E. Cattaneo,et al.  Role of brain-derived neurotrophic factor in Huntington's disease , 2007, Progress in Neurobiology.

[55]  Mark Turmaine,et al.  Formation of Neuronal Intranuclear Inclusions Underlies the Neurological Dysfunction in Mice Transgenic for the HD Mutation , 1997, Cell.

[56]  Jane S. Paulsen,et al.  Psychiatric Symptoms in Huntington’s Disease before Diagnosis: The Predict-HD Study , 2007, Biological Psychiatry.

[57]  R. S. Williams,et al.  Evidence for neuronal degeneration and dendritic plasticity in cortical pyramidal neurons of Huntington's disease , 1993, Neurology.

[58]  H. D. Rosas,et al.  Riluzole therapy in Huntington's disease (HD) , 1999, Movement disorders : official journal of the Movement Disorder Society.

[59]  E. Almqvist.  At risk for Huntington disease : The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled. , 2006 .

[60]  R. Roos,et al.  Adverse effects of predictive testing for Huntington disease underestimated: long-term effects 7-10 years after the test. , 2004, Health psychology : official journal of the Division of Health Psychology, American Psychological Association.

[61]  J. Gusella,et al.  De novo expansion of a (CAG)n repeat in sporadic Huntington's disease , 1993, Nature genetics.

[62]  R. Bonelli,et al.  A systematic review of the treatment studies in Huntington’s disease since 1990 , 2007, Expert opinion on pharmacotherapy.

[63]  R. Morimoto,et al.  The stress of misfolded proteins: C. elegans models for neurodegenerative disease and aging. , 2007, Advances in experimental medicine and biology.

[64]  J. Olson,et al.  Huntingtin Interacting Proteins Are Genetic Modifiers of Neurodegeneration , 2007, PLoS genetics.

[65]  B Fischl,et al.  Regional cortical thinning in preclinical Huntington disease and its relationship to cognition , 2005, Neurology.

[66]  Blair R. Leavitt,et al.  Caspase Cleavage of Mutant Huntingtin Precedes Neurodegeneration in Huntington's Disease , 2002, The Journal of Neuroscience.

[67]  T. Robins Wahlin,et al.  To know or not to know: a review of behaviour and suicidal ideation in preclinical Huntington's disease. , 2007, Patient Education and Counseling.

[68]  R. Carraway,et al.  Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons , 1995, Neuron.

[69]  Ninds Net-Pd Investigators.  A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. , 2006 .

[70]  N W Kowall,et al.  Proliferative and degenerative changes in striatal spiny neurons in Huntington's disease: a combined study using the section-Golgi method and calbindin D28k immunocytochemistry , 1991, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[71]  M. F. Beal,et al.  Creatine in Huntington disease is safe, tolerable, bioavailable in brain and reduces serum 8OH2′dG , 2006, Neurology.

[72]  R. Dubinsky.  No going home for hospitalized Huntington's disease patients , 2005, Movement disorders : official journal of the Movement Disorder Society.

[73]  D. Borchelt,et al.  Nuclear-targeting of mutant huntingtin fragments produces Huntington's disease-like phenotypes in transgenic mice. , 2004, Human molecular genetics.

[74]  M. Youdim,et al.  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 , 2004, Annals of the New York Academy of Sciences.

[75]  M. MacDonald,et al.  Widespread Disruption of Repressor Element-1 Silencing Transcription Factor/Neuron-Restrictive Silencer Factor Occupancy at Its Target Genes in Huntington's Disease , 2007, The Journal of Neuroscience.

[76]  S. Hersch,et al.  Histones associated with downregulated genes are hypo-acetylated in Huntington's disease models. , 2007, Human molecular genetics.

[77]  Blair R. Leavitt,et al.  Loss of Huntingtin-Mediated BDNF Gene Transcription in Huntington's Disease , 2001, Science.

[78]  D. Housman,et al.  Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila , 2001, Nature.

[79]  Fabrice P Cordelières,et al.  Histone Deacetylase 6 Inhibition Compensates for the Transport Deficit in Huntington's Disease by Increasing Tubulin Acetylation , 2007, The Journal of Neuroscience.

[80]  M. Hayden,et al.  Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract , 1996, Nature Genetics.

[81]  Ruth Luthi-Carter,et al.  Histone Deacetylase Inhibition by Sodium Butyrate Chemotherapy Ameliorates the Neurodegenerative Phenotype in Huntington's Disease Mice , 2003, The Journal of Neuroscience.

[82]  Jane S. Paulsen,et al.  A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length , 2004, Clinical genetics.

[83]  Elena Cattaneo,et al.  Loss of normal huntingtin function: new developments in Huntington's disease research , 2001, Trends in Neurosciences.

[84]  S. Schreiber,et al.  Small Molecule Enhancers of Rapamycin-Induced TOR Inhibition Promote Autophagy, Reduce Toxicity in Huntington’s Disease Models and Enhance Killing of Mycobacteria by Macrophages , 2007, Autophagy.

[85]  Richard T. Johnson.  Current Therapy in Neurologic Disease , 1997 .

[86]  D. Rubinsztein,et al.  Chemotherapy for the Brain: The Antitumor Antibiotic Mithramycin Prolongs Survival in a Mouse Model of Huntington's Disease , 2004, The Journal of Neuroscience.

[87]  G. Bates,et al.  Histone deacetylase inhibitors as therapeutics for polyglutamine disorders , 2006, Nature Reviews Neuroscience.

[88]  A. Young,et al.  Discovery of a Novel Small-Molecule Targeting Selective Clearance of Mutant Huntingtin Fragments , 2007, Journal of biomolecular screening.

[89]  A. Blamire,et al.  High-dose creatine therapy for Huntington disease: A 2-year clinical and MRS study , 2005, Neurology.

[90]  O. Andreassen,et al.  Lipoic acid improves survival in transgenic mouse models of Huntington's disease , 2001, Neuroreport.

[91]  Dimitri Krainc,et al.  Sp1 and TAFII130 Transcriptional Activity Disrupted in Early Huntington's Disease , 2002, Science.

[92]  Arne Klungland,et al.  OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells , 2007, Nature.

[93]  Paul W Goldberg,et al.  A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. , 1994, The New England journal of medicine.

[94]  J. Rothman,et al.  Autophagy-mediated clearance of huntingtin aggregates triggered by the insulin-signaling pathway , 2006, The Journal of cell biology.

[95]  A. Messer,et al.  Intrabody applications in neurological disorders: progress and future prospects. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[96]  Wayne R Matson,et al.  Dose ranging and efficacy study of high-dose coenzyme Q10 formulations in Huntington's disease mice. , 2006, Biochimica et biophysica acta.

[97]  S. W. Davies,et al.  Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. , 1997, Science.

[98]  A. Young,et al.  A small-molecule therapeutic lead for Huntington's disease: Preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse , 2007, Proceedings of the National Academy of Sciences.

[99]  Ole A. Andreassen,et al.  Therapeutic Effects of Coenzyme Q10 and Remacemide in Transgenic Mouse Models of Huntington's Disease , 2002, The Journal of Neuroscience.

[100]  S. Hersch.  Huntington's disease: prospects for neuroprotective therapy 10 years after the discovery of the causative genetic mutation , 2003, Current opinion in neurology.

[101]  O. Andreassen,et al.  Dichloroacetate exerts therapeutic effects in transgenic mouse models of Huntington's disease , 2001, Annals of neurology.

[102]  K. G. Rajeev,et al.  Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits , 2007, Proceedings of the National Academy of Sciences.

[103]  R. Elble,et al.  A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease , 2006, Neurology.

[104]  L. Raymond,et al.  Cleavage at the Caspase-6 Site Is Required for Neuronal Dysfunction and Degeneration Due to Mutant Huntingtin , 2006, Cell.

[105]  J. Olson,et al.  Expression Profiling of Huntington's Disease Models Suggests That Brain-Derived Neurotrophic Factor Depletion Plays a Major Role in Striatal Degeneration , 2007, The Journal of Neuroscience.

[106]  B. Davidson,et al.  RNAi: a potential therapy for the dominantly inherited nucleotide repeat diseases , 2006, Gene Therapy.

[107]  K. Fischbeck,et al.  CREB-binding protein sequestration by expanded polyglutamine. , 2000, Human molecular genetics.

[108]  David S Tuch,et al.  Diffusion tensor imaging in presymptomatic and early Huntington's disease: Selective white matter pathology and its relationship to clinical measures , 2006, Movement disorders : official journal of the Movement Disorder Society.

[109]  Jane S. Paulsen,et al.  Preparing for preventive clinical trials: the Predict-HD study. , 2006, Archives of neurology.

[110]  M. Hayden,et al.  Molecular analysis of new mutations for Huntington's disease: intermediate alleles and sex of origin effects , 1993, Nature genetics.

[111]  C A Ross,et al.  Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity , 2001, Science.

[112]  O. Isacson,et al.  Proteasome Activator Enhances Survival of Huntington's Disease Neuronal Model Cells , 2007, PloS one.

[113]  M. Mattson,et al.  Paroxetine retards disease onset and progression in Huntingtin mutant mice , 2004, Annals of neurology.

[114]  H. D. Rosas,et al.  The therapeutic role of creatine in Huntington's disease. , 2005, Pharmacology & therapeutics.

[115]  E. Hirsch,et al.  Cellular localization of the Huntington's disease protein and discrimination of the normal and mutated form , 1995, Nature Genetics.

[116]  B. Dubois,et al.  Riluzole in Huntington's disease: a 3‐year, randomized controlled study , 2007, Annals of neurology.

[117]  Dosage effects of riluzole in Huntington’s disease , 2003, Neurology.

[118]  R. Ferrante,et al.  Modulation of nucleosome dynamics in Huntington's disease. , 2007, Human molecular genetics.

[119]  R. Roos,et al.  Longitudinal evaluation of "presymptomatic" carriers of Huntington's disease. , 2007, The Journal of neuropsychiatry and clinical neurosciences.

[120]  S. Hersch,et al.  Therapeutic Effects of Cystamine in a Murine Model of Huntington's Disease , 2002, The Journal of Neuroscience.

[121]  S. Hersch,et al.  Ethyl-EPA in Huntington disease , 2005, Neurology.

[122]  Claire-Anne Gutekunst,et al.  Nuclear and Neuropil Aggregates in Huntington’s Disease: Relationship to Neuropathology , 1999, The Journal of Neuroscience.

[123]  S. Hersch.  At risk for Huntington disease: The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled. , 2006, Archives of neurology.

[124]  R. Bonelli,et al.  Apoptotic cascades as possible targets for inhibiting cell death in Huntington’s disease , 2006, Journal of Neurology.

[125]  M. Beal,et al.  PGC-1α, a New Therapeutic Target in Huntington's Disease? , 2006, Cell.

[126]  K. Caldwell,et al.  Ubiquitin conjugating enzymes participate in polyglutamine protein aggregation , 2007, BMC Cell Biology.

[127]  Elizabeth H. Aylward,et al.  Change in MRI striatal volumes as a biomarker in preclinical Huntington's disease , 2007, Brain Research Bulletin.

[128]  Sarah A. J. Reading,et al.  Functional brain changes in presymptomatic Huntington's disease , 2004, Annals of neurology.

[129]  M. Beal,et al.  Oxidative damage in Huntington's disease pathogenesis. , 2006, Antioxidants & redox signaling.

[130]  J. Cha,et al.  Mechanisms of Disease: histone modifications in Huntington's disease , 2006, Nature Clinical Practice Neurology.

[131]  Ole A. Andreassen,et al.  Neuroprotective Effects of Creatine in a Transgenic Mouse Model of Huntington's Disease , 2000, The Journal of Neuroscience.

[132]  S. Folstein,et al.  A controlled trial of idebenone in Huntington's disease , 1996, Movement disorders : official journal of the Movement Disorder Society.

[133]  J. O’Kusky,et al.  Toward Understanding the Molecular Pathology of Huntington's Disease , 1997, Brain pathology.

[134]  Jane S. Paulsen,et al.  Predictors of diagnosis in Huntington disease , 2007, Neurology.

[135]  P. Djian,et al.  Purification of neuronal inclusions of patients with Huntington's disease reveals a broad range of N‐terminal fragments of expanded huntingtin and insoluble polymers , 2005, Journal of neurochemistry.

[136]  D. Eidelberg,et al.  Book Review Movement Disorders: Neurologic principles and practice Edited by Ray L. Watts and William C. Koller. 779 pp., illustrated. New York, McGraw-Hill, 1997. $125. 0-07-035203-8 , 1997 .

[137]  R. Wetzel,et al.  Aggregated polyglutamine peptides delivered to nuclei are toxic to mammalian cells. , 2002, Human molecular genetics.

[138]  M. Vamos,et al.  The impact of Huntington's disease on family life. , 2007, Psychosomatics.

[139]  C. Steer,et al.  Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[140]  E A Zemskov,et al.  Altered proteasomal function due to the expression of polyglutamine-expanded truncated N-terminal huntingtin induces apoptosis by caspase activation through mitochondrial cytochrome c release. , 2001, Human molecular genetics.