Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Therapeutics development for triplet repeat expansion diseases

Nature Reviews Genetics volume 6, pages 756–766 (2005)Cite this article

Key Points

  • More than 20 diseases are caused by expansions of trinucleotide repeats. The expended repeats can be in either coding or non-coding DNA.

  • Friedreich ataxia is caused by a non-coding repeat expansion that leads to loss of the protein frataxin, accumulation of iron in mitochondria, increased susceptibility to oxidative stress, and a reduction in oxidative phosphorylation that is due to deficiency in mitochondrial proteins. Antioxidant therapy has had promising results and is currently being investigated in further clinical trials.

  • Repeat expansion in the 5′ UTR of the fragile X syndrome gene results in increased DNA methylation, reduced gene transcription and loss of the protein product FMR1. DNA demethylating agents and histone deacetylase (HDAC) inhibitors have had limited success in enhancing transcription in vitro. An antagonist of the group 1 metabotropic glutamate receptor ameliorates the phenotype in a Drosophila model of fragile X syndrome.

  • An expanded CTG repeat in the 3′ UTR of the dystrophia myotonica protein kinase (DMPK) gene probably causes the disease manifestations of dystrophia myotonica 1 by sequestering RNA-binding proteins. Ribozyme therapy to splice out the expanded region has had efficacy both in vitro and in vivo. Bioflavonoids can reduce cell toxicity in vitro, possibly through activation of class III HDACs.

  • Animal and cell-culture models of polyglutamine diseases show protein aggregation, caspase activation, excitotoxicity, oxidative stress and transcriptional dysregulation. Treatments that are based on these findings have shown efficacy in model systems. Combinatorial therapy using drugs with different targets might yield the most beneficial effects. Definitive therapy that is based on inactivation of the mutant gene still has technical barriers to overcome.

  • The triplet repeat expansion disorders have defined genetic defects, well-characterized cell-culture and animal models, and identified disease mechanisms that offer the opportunity for systematic approaches to the development of therapeutics.

Abstract

The underlying genetic mutations for many inherited neurodegenerative disorders have been identified in recent years. One frequent type of mutation is trinucleotide repeat expansion. Depending on the location of the repeat expansion, the mutation might result in a loss of function of the disease gene, a toxic gain of function or both. Disease gene identification has led to the development of model systems for investigating disease mechanisms and evaluating treatments. Examination of experimental findings reveals similarities in disease mechanisms as well as possibilities for treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Friedreich ataxia: pathogenesis and points of intervention.
Figure 2: Promoter inactivation and transcriptional repression in fragile X syndrome.
Figure 3: Mechanisms of toxicity in Huntington disease.

Similar content being viewed by others

References

  1. La Spada, A. R., Wilson, E. M., Lubahn, D. B., Harding, A. E. & Fischbeck, K. H. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 352, 77–79 (1991).

    Article  CAS  PubMed  Google Scholar 

  2. Cummings, C. J. & Zoghbi, H. Y. Fourteen and counting: unraveling trinucleotide repeat diseases. Hum. Mol. Genet. 9, 909–916 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Campuzano, V. et al. Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes. Hum. Mol. Genet. 6, 1771–1780 (1997).

    Article  CAS  PubMed  Google Scholar 

  4. Wilson, R. B. Frataxin and frataxin deficiency in Friedreich's ataxia. J. Neurol. Sci. 207, 103–105 (2003).

    Article  PubMed  Google Scholar 

  5. Pandolfo, M. Molecular basis of Friedreich ataxia. Mov. Disord. 16, 815–821 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Gillis, J. C., Benefield, P. & McTavish, D. Idebenone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in age-related cognitive disorders. Drugs Aging 5, 133–152 (1994).

    Article  CAS  PubMed  Google Scholar 

  7. Rotig, A., Sidi, D., Munnich, A. & Rustin, P. Molecular insights into Friedreich's ataxia and antioxidant-based therapies. Trends Mol. Med. 8, 221–224 (2002). This is a review of the consequences of frataxin loss and the rationale behind antioxidant therapy.

    Article  CAS  PubMed  Google Scholar 

  8. Artuch, R. et al. Friedreich's ataxia: idebenone treatment in early stage patients. Neuropediatrics 33, 190–193 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Gutzmann, H. & Hadler, D. Sustained efficacy and safety of idebenone in the treatment of Alzheimer's disease: update on a 2-year double-blind multicentre study. J. Neural Transm. Suppl. 54, 301–310 (1998).

    Article  CAS  PubMed  Google Scholar 

  10. Kelso, G. F. et al. Selective targeting of a redox-active ubiquinone to mitochondria within cells: antioxidant and antiapoptotic properties. J. Biol. Chem. 276, 4588–4596 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Jauslin, M. L., Meier, T., Smith, R. A. & Murphy, M. P. Mitochondria-targeted antioxidants protect Friedreich ataxia fibroblasts from endogenous oxidative stress more effectively than untargeted antioxidants. FASEB J. 17, 1972–1974 (2003).

    Article  CAS  PubMed  Google Scholar 

  12. Wardman, P. & Candeias, L. P. Fenton chemistry: an introduction. Radiat. Res. 145, 523–531 (1996).

    Article  CAS  PubMed  Google Scholar 

  13. Ponka, P., Borova, J., Neuwirt, J., Fuchs, O. & Necas, E. A study of intracellular iron metabolism using pyridoxal isonicotinoyl hydrazone and other synthetic chelating agents. Biochim. Biophys. Acta 586, 278–297 (1979).

    Article  CAS  PubMed  Google Scholar 

  14. Richardson, D. R., Mouralian, C., Ponka, P. & Becker, E. Development of potential iron chelators for the treatment of Friedreich's ataxia: ligands that mobilize mitochondrial iron. Biochim. Biophys. Acta 1536, 133–140 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Sarsero, J. P. et al. Upregulation of expression from the FRDA genomic locus for the therapy of Friedreich ataxia. J. Gene Med. 5, 72–81 (2003).

    Article  CAS  PubMed  Google Scholar 

  16. Ghazizadeh, M. Cisplatin may induce frataxin expression. J. Nippon Med. Sch. 70, 367–371 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Pieretti, M. et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 66, 817–822 (1991).

    Article  CAS  PubMed  Google Scholar 

  18. Chiurazzi, P., Pomponi, M. G., Willemsen, R., Oostra, B. A. & Neri, G. In vitro reactivation of the FMR1 gene involved in fragile X syndrome. Hum. Mol. Genet. 7, 109–113 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Pascale, E. et al. Modulation of methylation in the FMR1 promoter region after long term treatment with L-carnitine and acetyl-L-carnitine. J. Med. Genet. 40, e76 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Coffee, B., Zhang, F., Warren, S. T. & Reines, D. Acetylated histones are associated with FMR1 in normal but not fragile X-syndrome cells. Nature Genet. 22, 98–101 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Chiurazzi, P. et al. Synergistic effect of histone hyperacetylation and DNA demethylation in the reactivation of the FMR1 gene. Hum. Mol. Genet. 8, 2317–2323 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Nimchinsky, E. A., Oberlander, A. M. & Svoboda, K. Abnormal development of dendritic spines in FMR1 knock-out mice. J. Neurosci. 21, 5139–5146 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Irwin, S. A. et al. Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice. Am. J. Med. Genet. 111, 140–146 (2002).

    Article  PubMed  Google Scholar 

  24. Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bear, M. F., Huber, K. M. & Warren, S. T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004). The theory of excessive metabotropic receptor function in fragile X syndrome.

    Article  CAS  PubMed  Google Scholar 

  26. McBride, S. M. et al. Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 45, 753–764 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Meola, G. & Sansone, V. Treatment in myotonia and periodic paralysis. Rev. Neurol. 160, S55–S69 (2004).

    Article  CAS  PubMed  Google Scholar 

  28. Fu, Y. H. et al. An unstable triplet repeat in a gene related to myotonic muscular dystrophy. Science 255, 1256–1258 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Timchenko, N. A. et al. RNA CUG repeats sequester CUGBP1 and alter protein levels and activity of CUGBP1. J. Biol. Chem. 276, 7820–7826 (2001).

    Article  CAS  PubMed  Google Scholar 

  30. Phylactou, L. A., Darrah, C. & Wood, M. J. Ribozyme-mediated trans-splicing of a trinucleotide repeat. Nature Genet. 18, 378–381 (1998).

    Article  CAS  PubMed  Google Scholar 

  31. Furuya, H. et al. Some flavonoids and DHEA-S prevent the cis-effect of expanded CTG repeats in a stable PC12 cell transformant. Biochem. Pharmacol. 69, 503–516 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Scalbert, A., Johnson, I. T. & Saltmarsh, M. Polyphenols: antioxidants and beyond. Am. J. Clin. Nutr. 81, S215–S217 (2005).

    Article  Google Scholar 

  33. Howitz, K. T. et al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature 425, 191–196 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Parker, J. A. et al. Resveratrol rescues mutant polyglutamine cytotoxicity in nematode and mammalian neurons. Nature Genet. 37, 349–350 (2005). This paper describes HDAC (sirtuin family) activation as a means of suppressing polyglutamine toxicity.

    Article  CAS  PubMed  Google Scholar 

  35. Reddy, P. H. et al. Behavioural abnormalities and selective neuronal loss in HD transgenic mice expressing mutated full-length HD cDNA. Nature Genet. 20, 198–202 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Sato, T. et al. Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients. Hum. Mol. Genet. 8, 99–106 (1999).

    Article  CAS  PubMed  Google Scholar 

  37. Katsuno, M. et al. Testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Neuron 35, 843–854 (2002). The authors describe the ligand-dependent toxicity of the mutant androgen receptor in Kennedy disease. This emphasizes the need to understand each polyglutamine disorder in the context of the disease protein's normal function.

    Article  CAS  PubMed  Google Scholar 

  38. Reiner, A., Dragatsis, I., Zeitlin, S. & Goldowitz, D. Wild-type huntingtin plays a role in brain development and neuronal survival. Mol. Neurobiol. 28, 259–276 (2003).

    Article  CAS  PubMed  Google Scholar 

  39. Cattaneo, E. Dysfunction of wild-type huntingtin in Huntington disease. News Physiol. Sci. 18, 34–37 (2003).

    CAS  PubMed  Google Scholar 

  40. Cummings, C. J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148–154 (1998).

    Article  CAS  PubMed  Google Scholar 

  41. Chai, Y., Koppenhafer, S. L., Shoesmith, S. J., Perez, M. K. & Paulson, H. L. Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro. Hum. Mol. Genet. 8, 673–682 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Kazemi-Esfarjani, P. & Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837–1840 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Wyttenbach, A. et al. Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Proc. Natl Acad. Sci. USA 97, 2898–2903 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Sittler, A. et al. Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington's disease. Hum. Mol. Genet. 10, 1307–1315 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Heiser, V. et al. Identification of benzothiazoles as potential polyglutamine aggregation inhibitors of Huntington's disease by using an automated filter retardation assay. Proc. Natl Acad. Sci. USA 99, 16400–16406 (2002). This paper describes the application of high-throughput screening for polyglutamine disorders and shows that inhibitors of aggregation are therapeutic targets.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Smith, D. L. et al. Inhibition of polyglutamine aggregation in R6/2 HD brain slices-complex dose-response profiles. Neurobiol. Dis. 8, 1017–1026 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Sanchez, I., Mahlke, C. & Yuan, J. Pivotal role of oligomerization in expanded polyglutamine neurodegenerative disorders. Nature 421, 373–379 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Tanaka, M. et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. Nature Med. 10, 148–154 (2004). The authors discuss an approach to inhibiting protein aggregation using a saccharide–polyglutamine interaction. The safety profile of this chemical seems exceptionally favourable.

    Article  CAS  PubMed  Google Scholar 

  49. Khoshnan, A., Ko, J. & Patterson, P. H. Effects of intracellular expression of anti-huntingtin antibodies of various specificities on mutant huntingtin aggregation and toxicity. Proc. Natl Acad. Sci. USA 99, 1002–1007 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kazantsev, A. et al. A bivalent Huntingtin binding peptide suppresses polyglutamine aggregation and pathogenesis in Drosophila. Nature Genet. 30, 367–376 (2002).

    Article  CAS  PubMed  Google Scholar 

  51. Kahlem, P., Terre, C., Green, H. & Djian, P. Peptides containing glutamine repeats as substrates for transglutaminase-catalyzed cross-linking: relevance to diseases of the nervous system. Proc. Natl Acad. Sci. USA 93, 14580–14585 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Karpuj, M. V. et al. Transglutaminase aggregates huntingtin into nonamyloidogenic polymers, and its enzymatic activity increases in Huntington's disease brain nuclei. Proc. Natl Acad. Sci. USA 96, 7388–7393 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Dedeoglu, A. et al. Therapeutic effects of cystamine in a murine model of Huntington's disease. J. Neurosci. 22, 8942–8950 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Karpuj, M. V. et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. Nature Med. 8, 143–149 (2002). This article provides an example of effective treatment after the development of disease manifestations. It also describes activity of the drug outside its pharmacological target.

    Article  CAS  PubMed  Google Scholar 

  55. Lesort, M., Lee, M., Tucholski, J. & Johnson, G. V. Cystamine inhibits caspase activity. Implications for the treatment of polyglutamine disorders. J. Biol. Chem. 278, 3825–3830 (2003).

    Article  CAS  PubMed  Google Scholar 

  56. Bailey, C. D. & Johnson, G. V. Tissue transglutaminase contributes to disease progression in the R6/2 Huntington's disease mouse model via aggregate-independent mechanisms. J. Neurochem. 92, 83–92 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Wellington, C. L. & Hayden, M. R. Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches. Clin. Genet. 57, 1–10 (2000).

    Article  CAS  PubMed  Google Scholar 

  58. Goldberg, Y. P. et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nature Genet. 13, 442–449 (1996).

    Article  CAS  PubMed  Google Scholar 

  59. Wellington, C. L. et al. Caspase cleavage of gene products associated with triplet expansion disorders generates truncated fragments containing the polyglutamine tract. J. Biol. Chem. 273, 9158–9167 (1998).

    Article  CAS  PubMed  Google Scholar 

  60. Wellington, C. L. et al. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J. Biol. Chem. 275, 19831–19838 (2000).

    Article  CAS  PubMed  Google Scholar 

  61. Ona, V. O. et al. Inhibition of caspase-1 slows disease progression in a mouse model of Huntington's disease. Nature 399, 263–267 (1999).

    Article  CAS  PubMed  Google Scholar 

  62. Chen, M. et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nature Med. 6, 797–801 (2000). The authors describe the amelioration of disease manifestations in an HD model with a drug that inhibits caspase.

    Article  CAS  PubMed  Google Scholar 

  63. Wang, X. et al. Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Huntington's disease. Proc. Natl Acad. Sci. USA 100, 10483–10487 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Bonelli, R. M., Hodl, A. K., Hofmann, P. & Kapfhammer, H. P. Neuroprotection in Huntington's disease: a 2-year study on minocycline. Int. Clin. Psychopharmacol. 19, 337–342 (2004).

    Article  PubMed  Google Scholar 

  65. Keene, C. D. et al. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington's disease. Proc. Natl Acad. Sci. USA 99, 10671–10676 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Coyle, J. T. & Schwarcz, R. Lesion of striatal neurones with kainic acid provides a model for Huntington's chorea. Nature 263, 244–246 (1976).

    Article  CAS  PubMed  Google Scholar 

  67. Beal, M. F. et al. Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature 321, 168–171 (1986).

    Article  CAS  PubMed  Google Scholar 

  68. Cepeda, C. et al. NMDA receptor function in mouse models of Huntington disease. J. Neurosci. Res. 66, 525–539 (2001).

    Article  CAS  PubMed  Google Scholar 

  69. Zeron, M. M. et al. Increased sensitivity to N-methyl-D-aspartate receptor-mediated excitotoxicity in a mouse model of Huntington's disease. Neuron 33, 849–860 (2002).

    Article  CAS  PubMed  Google Scholar 

  70. Nicniocaill, B., Haraldsson, B., Hansson, O., O'Connor, W. T. & Brundin, P. Altered striatal amino acid neurotransmitter release monitored using microdialysis in R6/1 Huntington transgenic mice. Eur. J. Neurosci. 13, 206–210 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. Li, J. Y., Plomann, M. & Brundin, P. Huntington's disease: a synaptopathy? Trends Mol. Med. 9, 414–420 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Cha, J. H. et al. Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease. Phil. Trans. R. Soc. Lond. B 354, 981–989 (1999).

    Article  CAS  Google Scholar 

  73. O'Suilleabhain, P. & Dewey, R. B. Jr. A randomized trial of amantadine in Huntington disease. Arch. Neurol. 60, 996–998 (2003).

    Article  PubMed  Google Scholar 

  74. Lucetti, C. et al. Amantadine in Huntington's disease: open-label video-blinded study. Neurol. Sci. 23, S83–S84 (2002).

    Article  PubMed  Google Scholar 

  75. Verhagen Metman, L. et al. Huntington's disease: a randomized, controlled trial using the NMDA-antagonist amantadine. Neurology 59, 694–699 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Murman, D. L. et al. Cognitive, behavioral, and motor effects of the NMDA antagonist ketamine in Huntington's disease. Neurology 49, 153–161 (1997).

    Article  CAS  PubMed  Google Scholar 

  77. Shoulson, I. et al. A controlled clinical trial of baclofen as protective therapy in early Huntington's disease. Ann. Neurol. 25, 252–259 (1989).

    Article  CAS  PubMed  Google Scholar 

  78. Kremer, B. et al. Influence of lamotrigine on progression of early Huntington disease: a randomized clinical trial. Neurology 53, 1000–1011 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Seppi, K. et al. Riluzole in Huntington's disease (HD): an open label study with one year follow up. J. Neurol. 248, 866–869 (2001).

    Article  CAS  PubMed  Google Scholar 

  80. Li, L. et al. Role of NR2B-type NMDA receptors in selective neurodegeneration in Huntington disease. Neurobiol. Aging 24, 1113–1121 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. Li, L., Murphy, T. H., Hayden, M. R. & Raymond, L. A. Enhanced striatal NR2B-containing N-methyl-D-aspartate receptor-mediated synaptic currents in a mouse model of Huntington disease. J. Neurophysiol. 92, 2738–2746 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Arning, L. et al. NR2A and NR2B receptor gene variations modify age of onset in Huntington's disease. Neurogenetics 6, 25–28 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Chen, H. S. & Lipton, S. A. Mechanism of memantine block of NMDA-activated channels in rat retinal ganglion cells: uncompetitive antagonism. J. Physiol. 499, 27–46 (1997).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Beister, A. et al. The N-methyl-D-aspartate antagonist memantine retards progression of Huntington's disease. J. Neural Transm. 68, S117–S122 (2004).

    Google Scholar 

  85. Nicoletti, F. et al. Group-I metabotropic glutamate receptors: hypotheses to explain their dual role in neurotoxicity and neuroprotection. Neuropharmacology 38, 1477–1484 (1999).

    Article  CAS  PubMed  Google Scholar 

  86. Schiefer, J. et al. The metabotropic glutamate receptor 5 antagonist MPEP and the mGluR2 agonist LY379268 modify disease progression in a transgenic mouse model of Huntington's disease. Brain Res. 1019, 246–254 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Popoli, P. et al. Blockade of striatal adenosine A2A receptor reduces, through a presynaptic mechanism, quinolinic acid-induced excitotoxicity: possible relevance to neuroprotective interventions in neurodegenerative diseases of the striatum. J. Neurosci. 22, 1967–1975 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Lastres-Becker, I. et al. Effects of cannabinoids in the rat model of Huntington's disease generated by an intrastriatal injection of malonate. Neuroreport 14, 813–816 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Borlongan, C. V. et al. Systemic 3-nitropropionic acid: behavioral deficits and striatal damage in adult rats. Brain Res. Bull. 36, 549–556 (1995).

    Article  CAS  PubMed  Google Scholar 

  90. Gu, M. et al. Mitochondrial defect in Huntington's disease caudate nucleus. Ann. Neurol. 39, 385–389 (1996).

    Article  CAS  PubMed  Google Scholar 

  91. Browne, S. E. et al. Oxidative damage and metabolic dysfunction in Huntington's disease: selective vulnerability of the basal ganglia. Ann. Neurol. 41, 646–653 (1997).

    Article  CAS  PubMed  Google Scholar 

  92. Beal, M. F. & Ferrante, R. J. Experimental therapeutics in transgenic mouse models of Huntington's disease. Nature Rev. Neurosci. 5, 373–384 (2004). A review of the pathogenesis of HD in the context of mouse models and the efficacy of therapeutic agents tested in these models.

    Article  CAS  Google Scholar 

  93. Dedeoglu, A. et al. Creatine therapy provides neuroprotection after onset of clinical symptoms in Huntington's disease transgenic mice. J. Neurochem. 85, 1359–1367 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Verbessem, P. et al. Creatine supplementation in Huntington's disease: a placebo-controlled pilot trial. Neurology 61, 925–930 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Huntington Study Group. A randomized, placebo-controlled trial of coenzyme Q10 and remacemide in Huntington's disease. Neurology 57, 397–404 (2001).

  96. Ranen, N. G. et al. A controlled trial of idebenone in Huntington's disease. Mov. Disord. 11, 549–554 (1996).

    Article  CAS  PubMed  Google Scholar 

  97. Okazawa, H. Polyglutamine diseases: a transcription disorder? Cell. Mol. Life Sci. 60, 1427–1439 (2003).

    Article  CAS  PubMed  Google Scholar 

  98. McCampbell, A. et al. CREB-binding protein sequestration by expanded polyglutamine. Hum. Mol. Genet. 9, 2197–2202 (2000).

    Article  CAS  PubMed  Google Scholar 

  99. Dunah, A. W. et al. Sp1 and TAFII130 transcriptional activity disrupted in early Huntington's disease. Science 296, 2238–2243 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Taylor, J. P. et al. Aberrant histone acetylation, altered transcription, and retinal degeneration in a Drosophila model of polyglutamine disease are rescued by CREB-binding protein. Genes Dev. 17, 1463–1468 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  101. Grewal, S. I. & Moazed, D. Heterochromatin and epigenetic control of gene expression. Science 301, 798–802 (2003).

    Article  CAS  PubMed  Google Scholar 

  102. Steffan, J. S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739–743 (2001). This is a description of reduced acetyltransferase activity and histone acetylation in polyglutamine disease, and how this can be overcome by HDAC inhibitors with consequent amelioration of toxicity.

    Article  CAS  PubMed  Google Scholar 

  103. Igarashi, S. et al. Inducible PC12 cell model of Huntington's disease shows toxicity and decreased histone acetylation. Neuroreport 14, 565–568 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Hockly, E. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl Acad. Sci. USA 100, 2041–2046 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington's disease mice. J. Neurosci. 23, 9418–9427 (2003). This article discusses the beneficial effects of HDAC inhibitors in an HD mouse model.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gottlicher, M. Valproic acid: an old drug newly discovered as inhibitor of histone deacetylases. Ann. Hematol. 83 (Suppl. 1), 91–92 (2004).

    Google Scholar 

  107. Burlina, A. B., Ogier, H., Korall, H. & Trefz, F. K. Long-term treatment with sodium phenylbutyrate in ornithine transcarbamylase-deficient patients. Mol. Genet. Metab. 72, 351–355 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Kelly, W. K., O'Connor, O. A. & Marks, P. A. Histone deacetylase inhibitors: from target to clinical trials. Expert Opin. Investig. Drugs 11, 1695–1713 (2002).

    Article  CAS  PubMed  Google Scholar 

  109. Brunet, A. et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 303, 2011–2015 (2004).

    Article  CAS  PubMed  Google Scholar 

  110. Emerich, D. F. et al. Implants of polymer-encapsulated human NGF-secreting cells in the nonhuman primate: rescue and sprouting of degenerating cholinergic basal forebrain neurons. J. Comp. Neurol. 349, 148–164 (1994).

    Article  CAS  PubMed  Google Scholar 

  111. Emerich, D. F. et al. Implants of encapsulated human CNTF-producing fibroblasts prevent behavioral deficits and striatal degeneration in a rodent model of Huntington's disease. J. Neurosci. 16, 5168–5181 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Bemelmans, A. P. et al. Brain-derived neurotrophic factor-mediated protection of striatal neurons in an excitotoxic rat model of Huntington's disease, as demonstrated by adenoviral gene transfer. Hum. Gene Ther. 10, 2987–2997 (1999).

    Article  CAS  PubMed  Google Scholar 

  113. Perez-Navarro, E., Canudas, A. M., Akerund, P., Alberch, J. & Arenas, E. Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington's disease. J. Neurochem. 75, 2190–2199 (2000).

    Article  CAS  PubMed  Google Scholar 

  114. McBride, J. L. et al. Structural and functional neuroprotection in a rat model of Huntington's disease by viral gene transfer of GDNF. Exp. Neurol. 181, 213–223 (2003).

    Article  CAS  PubMed  Google Scholar 

  115. Kells, A. P. et al. AAV-mediated gene delivery of BDNF or GDNF is neuroprotective in a model of Huntington disease. Mol. Ther. 9, 682–688 (2004).

    Article  CAS  PubMed  Google Scholar 

  116. Canals, J. M. et al. Brain-derived neurotrophic factor regulates the onset and severity of motor dysfunction associated with enkephalinergic neuronal degeneration in Huntington's disease. J. Neurosci. 24, 7727–7739 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Cepeda, C. et al. Increased GABAergic function in mouse models of Huntington's disease: reversal by BDNF. J. Neurosci. Res. 78, 855–867 (2004).

    Article  CAS  PubMed  Google Scholar 

  118. Popovic, N., Maingay, M., Kirik, D. & Brundin, P. Lentiviral gene delivery of GDNF into the striatum of R6/2 Huntington mice fails to attenuate behavioral and neuropathological changes. Exp. Neurol. 193, 65–74 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Zuccato, C. et al. Loss of huntingtin-mediated BDNF gene transcription in Huntington's disease. Science 293, 493–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  120. Sopher, B. L. et al. Androgen receptor YAC transgenic mice recapitulate SBMA motor neuronopathy and implicate VEGF164 in the motor neuron degeneration. Neuron 41, 687–699 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. 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).

    Article  CAS  PubMed  Google Scholar 

  122. Dunnett, S. B. et al. Striatal transplantation in a transgenic mouse model of Huntington's disease. Exp. Neurol. 154, 31–40 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. van Dellen, A., Deacon, R., York, D., Blakemore, C. & Hannan, A. J. Anterior cingulate cortical transplantation in transgenic Huntington's disease mice. Brain Res. Bull. 56, 313–318 (2001).

    Article  CAS  PubMed  Google Scholar 

  124. Freeman, T. B. et al. Transplanted fetal striatum in Huntington's disease: phenotypic development and lack of pathology. Proc. Natl Acad. Sci. USA 97, 13877–13882 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Bachoud-Levi, A. C. et al. Motor and cognitive improvements in patients with Huntington's disease after neural transplantation. Lancet 356, 1975–1979 (2000).

    Article  CAS  PubMed  Google Scholar 

  126. Gaura, V. et al. Striatal neural grafting improves cortical metabolism in Huntington's disease patients. Brain 127, 65–72 (2004).

    Article  PubMed  Google Scholar 

  127. McBride, J. L. et al. Human neural stem cell transplants improve motor function in a rat model of Huntington's disease. J. Comp. Neurol. 475, 211–219 (2004).

    Article  PubMed  Google Scholar 

  128. Lescaudron, L., Unni, D. & Dunbar, G. L. Autologous adult bone marrow stem cell transplantation in an animal model of huntington's disease: behavioral and morphological outcomes. Int. J. Neurosci. 113, 945–956 (2003).

    Article  PubMed  Google Scholar 

  129. Ende, N. & Chen, R. Human umbilical cord blood cells ameliorate Huntington's disease in transgenic mice. J. Med. 32, 231–240 (2001).

    CAS  PubMed  Google Scholar 

  130. Yamamoto, A., Lucas, J. J. & Hen, R. Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57–66 (2000). The authors show that blockade of expression of the mutant protein leads to a disappearance of inclusions and a reversal of the behavioural phenotype. This indicates that continuous expression of the mutant protein is necessary for the disease.

    Article  CAS  PubMed  Google Scholar 

  131. Caplen, N. J. et al. Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. Hum. Mol. Genet. 11, 175–184 (2002).

    Article  CAS  PubMed  Google Scholar 

  132. Xia, H. et al. RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nature Med. 10, 816–820 (2004). A discussion of in vivo use of RNAi as a potential therapy for dominant neurodegenerative disorders.

    Article  CAS  PubMed  Google Scholar 

  133. Harper, S. Q. et al. RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proc. Natl Acad. Sci. USA 102, 5820–5825 (2005). This paper shows that RNAi can accomplish disease allele-specific silencing in vivo.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Ravina, B. M. et al. Neuroprotective agents for clinical trials in Parkinson's disease: a systematic assessment. Neurology 60, 1234–1240 (2003).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute of General Medical Sciences (NIGMS) at the US National Institutes of Health. N.A.D. is supported under a clinical pharmacology research associate training fellowship awarded by NIGMS.

Author information

Authors and Affiliations

  1. Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, 20892-3705, Maryland, USA

    Nicholas A. Di Prospero & Kenneth H. Fischbeck

Authors
  1. Nicholas A. Di Prospero
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kenneth H. Fischbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicholas A. Di Prospero.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

BDNF

CNTF

CREBBP

DMPK

FMR1

GDNF

PCAF

SP1

TAF4

VEGF

MedlinePlus

Amantadine

Cysteamine

Idebenone

Memantine

Minocycline

Tauroursodeoxycholic acid

Ubiquinone

OMIM

Fragile X syndrome

Friedreich´s ataxia

Huntington disease

Dystrophia myotonica 1

Parkinson disease

Spinal and bulbar muscular atrophy

Spinocerebellar ataxia 1

FURTHER INFORMATION

FRAXA—The Fragile X Research Foundation

Friedreich's Ataxia Research Alliance

Hereditary Disease Foundation

Huntington Study Group

Muscular Dystrophy Association

Glossary

OPEN-LABEL TRIAL

A clinical trial in which both subjects and investigators know which drug is being tested and the doses that are being used.

DOUBLE-BLIND TRIAL

A study in which neither the investigator nor the subject know whether a medication or placebo is being used for any given subject, so as to prevent subjective bias on the part of the subject or investigator.

PLACEBO-CONTROLLED

The use of an inactive substance or treatment that seems to be the same as, and is given in the same way as, an active drug or treatment being tested. The effects of the active drug or treatment are compared with the effects of the placebo.

PHASE II CLINICAL TRIAL

A study that is carried out to obtain more safety data and preliminary data on the effectiveness of the drug for a particular indication in patients with the disease or condition. Phase II studies help to determine the feasibility of larger-scale definitive trials.

PHASE I CLINICAL TRIAL

An initial clinical study that involves small numbers of healthy human volunteers and small doses to assess safety, metabolism and excretion of a drug.

LYMPHOBLASTS

Immature white blood cells.

DENDRITES

Short and typically highly branched extensions of the neuronal cell body that form synaptic contacts with the terminals of other neurons and allow the transmission of nerve impulses between cells.

MYOTONIA

The failure of muscle to relax immediately after voluntary contraction has stopped.

ANTICIPATION

The tendency of certain diseases to have an earlier age of onset and increasing severity in successive generations.

PROTEASOME

A cytosolic protein complex that degrades proteins that have been marked for destruction by the ubiquitylation pathway.

CORTEX

The superficial layer of grey matter that is involved in higher functions, including initiation of voluntary movements, cognition and emotion.

STRIATUM

The region of the brain that receives excitatory input from the cortex, thalamus and midbrain. It has a pivotal role in modulating motor activity and higher cognitive function.

STRIATAL PROJECTION NEURONS

These are medium sized, GABA-containing neurons of the striatum that project to the substantia nigra and have an important role in the regulation of movement.

PHASE III CLINICAL TRIAL

A study that is intended to gather the extra information about effectiveness and safety that is needed to evaluate the overall benefit–risk relationship of the drug. Phase III studies also provide a basis for extrapolating the results to the general population.

RESVERATROL

A natural compound that is found in grapes, mulberries, peanuts and other plants or food products, especially red wine, that has antioxidant, antimutagen and anti-inflammatory properties.

PET SCAN

A positron emission tomography scan. This is an imaging technique that relies on the detection of γ-rays that are emitted from tissues after the administration of a natural biochemical substance into which positron-emitting isotopes have been incorporated.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Di Prospero, N., Fischbeck, K. Therapeutics development for triplet repeat expansion diseases. Nat Rev Genet 6, 756–766 (2005). https://doi.org/10.1038/nrg1690

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrg1690

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing