Hostname: page-component-77c89778f8-gq7q9 Total loading time: 0 Render date: 2024-07-17T08:37:36.871Z Has data issue: false hasContentIssue false
  • English
  • Français

RNA therapy for polyglutamine neurodegenerative diseases

Published online by Cambridge University Press:  31 January 2012

Lauren M. Watson  and
Matthew J. A. Wood
Lauren M. Watson
Affiliation:
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK Division of Human Genetics, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
Matthew J. A. Wood*
Affiliation:
Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK
*
*Corresponding author: Matthew J. A. Wood, Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK. E-mail: matthew.wood@dpag.ox.ac.uk
Get access Rights & Permissions [Opens in a new window]

Abstract

Polyglutamine neurodegenerative diseases result from the expansion of a trinucleotide CAG repeat, encoding a polyglutamine tract in the disease-causing protein. The process by which each polyglutamine protein exerts its toxicity is complex, involving a variety of mechanisms including transcriptional dysregulation, proteasome impairment and mitochondrial dysfunction. Thus, the most effective and widely applicable therapies are likely to be those designed to eliminate production of the mutant protein upstream of these deleterious effects. RNA-based approaches represent promising therapeutic strategies for polyglutamine diseases, offering the potential to suppress gene expression in a sequence-specific manner at the transcriptional and post-transcriptional levels. In particular, gene silencing therapies capable of discrimination between mutant and wildtype alleles, based on disease-linked polymorphisms or CAG repeat length, might prove crucial in cases where a loss of wild type function is deleterious. Novel methods, such as gene knockdown and replacement, seek to eliminate the technical difficulties associated with allele-specific silencing by avoiding the need to target specific mutations. With a variety of RNA technologies currently being developed to target multiple facets of polyglutamine pathogenesis, the emergence of an effective therapy seems imminent. However, numerous technical obstacles associated with design, discrimination and delivery must be overcome before RNA therapy can be effectively applied in the clinical setting.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e3
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Durr, A. (2010) Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurology 9, 885-894CrossRefGoogle ScholarPubMed
2Stevanin, G. et al. (1998) De novo expansion of intermediate alleles in spinocerebellar ataxia 7. Human Molecular Genetics 7, 1809-1813CrossRefGoogle ScholarPubMed
3Garden, G.A. and La Spada, A.R. (2007) Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum 99999, 1-12CrossRefGoogle Scholar
4Globas, C. et al. (2008) Early symptoms in spinocerebellar ataxia type 1, 2, 3, and 6. Movement Disorders 23, 2232-2238CrossRefGoogle Scholar
5Lebre, A.S. and Brice, A. (2003) Spinocerebellar ataxia 7 (SCA7). Cytogenetic Genome Research 100, 154-163CrossRefGoogle ScholarPubMed
6Pulst, S.M. et al. (2005) Spinocerebellar ataxia type 2: polyQ repeat variation in the CACNA1A calcium channel modifies age of onset. Brain 128, 2297-2303CrossRefGoogle ScholarPubMed
7Li, S.H. and Li, X.J. (2004) Huntingtin-protein interactions and the pathogenesis of Huntington's disease. Trends in Genetics 20, 146-154CrossRefGoogle ScholarPubMed
8Saegusa, H. et al. (2007) Properties of human Cav2. 1 channel with a spinocerebellar ataxia type 6 mutation expressed in Purkinje cells. Molecular and Cellular Neuroscience 34, 261-270CrossRefGoogle ScholarPubMed
9La Spada, A.R. et al. (2001) Polyglutamine-expanded ataxin-7 antagonizes CRX function and induces cone-rod dystrophy in a mouse model of SCA7. Neuron 31, 913-927CrossRefGoogle Scholar
10Helmlinger, D. et al. (2006) Glutamine-expanded ataxin-7 alters TFTC/STAGA recruitment and chromatin structure leading to photoreceptor dysfunction. PLoS Biology 4, 432-445CrossRefGoogle ScholarPubMed
11Yoo, S.Y. et al. (2003) SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity. Neuron 37, 383-401CrossRefGoogle ScholarPubMed
12Bichelmeier, U. et al. (2007) Nuclear localization of ataxin-3 is required for the manifestation of symptoms in SCA3: in vivo evidence. Journal of Neuroscience 27, 7418-7428CrossRefGoogle ScholarPubMed
13Burright, E.N. et al. (1995) SCA1 transgenic mice: a model for neurodegeneration caused by an expanded CAG trinucleotide repeat. Cell 82, 937-948CrossRefGoogle Scholar
14Goti, D. et al. (2004) A mutant ataxin-3 putative-cleavage fragment in brains of Machado-Joseph disease patients and transgenic mice is cytotoxic above a critical concentration. Journal of Neuroscience 24, 10266-10279CrossRefGoogle ScholarPubMed
15Watase, K. et al. (2002) A long CAG repeat in the mouse Sca1 locus replicates SCA1 features and reveals the impact of protein solubility on selective neurodegeneration. Neuron 34, 905-919CrossRefGoogle ScholarPubMed
16Huynh, D.P. et al. (2003) Expansion of the polyQ repeat in ataxin-2 alters its Golgi localization, disrupts the Golgi complex and causes cell death. Human Molecular Genetics 12, 1485-1496CrossRefGoogle ScholarPubMed
17Cemal, C.K. et al. (2002) YAC transgenic mice carrying pathological alleles of the MJD1 locus exhibit a mild and slowly progressive cerebellar deficit. Human Molecular Genetics 11, 1075-1094CrossRefGoogle ScholarPubMed
18Shirendeb, U. et al. (2011) Abnormal mitochondrial dynamics, mitochondrial loss and mutant huntingtin oligomers in Huntington's disease: implications for selective neuronal damage. Human Molecular Genetics 20, 1438-1455CrossRefGoogle ScholarPubMed
19Yamanaka, T. and Nukina, N. (2010) Transcription factor sequestration by polyglutamine proteins. Methods in Molecular Biology (Clifton, NJ) 648, 215-229CrossRefGoogle ScholarPubMed
20Sugars, K.L. and Rubinsztein, D.C. (2003) Transcriptional abnormalities in Huntington disease. Trends in Genetics 19, 233-238CrossRefGoogle ScholarPubMed
21Einum, D.D. et al. (2001) Ataxin-7 expression analysis in controls and spinocerebellar ataxia type 7 patients. Neurogenetics 3, 83-90CrossRefGoogle ScholarPubMed
22Carlson, K.M., Andresen, J.M. and Orr, H.T. (2009) Emerging pathogenic pathways in the spinocerebellar ataxias. Current Opinion in Genetics and Development 19, 247-253CrossRefGoogle ScholarPubMed
23Duenas, A.M., Goold, R. and Giunti, P. (2006) Molecular pathogenesis of spinocerebellar ataxias. Brain 129, 1357-1370CrossRefGoogle ScholarPubMed
24Shao, J. and Diamond, M.I. (2007) Polyglutamine diseases: emerging concepts in pathogenesis and therapy. Human Molecular Genetics 16, R115-R123CrossRefGoogle ScholarPubMed
25Palhan, V.B. et al. (2005) Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proceedings of the National Academy of Sciences of the United States of America 102, 8472-8477CrossRefGoogle ScholarPubMed
26Zoghbi, H.Y. and Orr, H.T. (2009) Pathogenic mechanisms of a polyglutamine-mediated neurodegenerative disease, spinocerebellar ataxia type 1. Journal of Biological Chemistry 284, 7425-7429CrossRefGoogle ScholarPubMed
27Kim, M.O. et al. (2008) Altered histone monoubiquitylation mediated by mutant huntingtin induces transcriptional dysregulation. Journal of Neuroscience 28, 3947-3957CrossRefGoogle ScholarPubMed
28Yvert, G. et al. (2001) SCA7 mouse models show selective stabilization of mutant ataxin-7 and similar cellular responses in different neuronal cell types. Human Molecular Genetics 10, 1679-1692CrossRefGoogle ScholarPubMed
29Young, J.E. et al. (2009) Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk. Journal of Neuroscience 29, 1987-1997CrossRefGoogle ScholarPubMed
30Colomer Gould, V.F. et al. (2007) A mutant ataxin-3 fragment results from processing at a site N-terminal to amino acid 190 in brain of Machado-Joseph disease-like transgenic mice. Neurobiology of Disease 27, 362-369CrossRefGoogle Scholar
31Jung, J. et al. (2009) Preventing ataxin-3 protein cleavage mitigates degeneration in a drosophila model of SCA3. Human Molecular Genetics 18, 4843-4852CrossRefGoogle Scholar
32Landles, C. et al. (2010) Proteolysis of mutant huntingtin produces an exon 1 fragment that accumulates as an aggregated protein in neuronal nuclei in Huntington disease. Journal of Biological Chemistry 285, 8808-8823CrossRefGoogle ScholarPubMed
33Clemens, L.E. et al. (2010) A14 fast axonal transport of mitochondria is altered in Huntington's disease. Journal of Neurology, Neurosurgery and Psychiatry 81, A5CrossRefGoogle Scholar
34Bennett, E.J. et al. (2007) Global changes to the ubiquitin system in Huntington's disease. Nature 448, 704-708CrossRefGoogle Scholar
35Bence, N.F., Sampat, R.M. and Kopito, R.R. (2001) Impairment of the ubiquitin-proteasome system by protein aggregation. Science 292, 1552-1555CrossRefGoogle ScholarPubMed
36Jana, N.R. (2010) Role of the ubiquitin–proteasome system and autophagy in polyglutamine neurodegenerative diseases. Future Neurology 5, 105-112CrossRefGoogle Scholar
37Drouet, V. et al. (2009) Sustained effects of nonallele-specific Huntingtin silencing. Annals of Neurology 65, 276-285CrossRefGoogle ScholarPubMed
38Boudreau, R.L. and Davidson, B.L. (2010) RNAi therapeutics for CNS disorders. Brain Research 1338, 112-121CrossRefGoogle ScholarPubMed
39Hasholt, L. et al. (2003) Antisense downregulation of mutant huntingtin in a cell model. Journal of Gene Medicine 5, 528-538CrossRefGoogle ScholarPubMed
40Bauer, P.O. and Nukina, N. (2009) The pathogenic mechanisms of polyglutamine diseases and current therapeutic strategies. Journal of Neurochemistry 110, 1737-1765CrossRefGoogle ScholarPubMed
41Xia, H. et al. (2002) siRNA-mediated gene silencing in vitro and in vivo. Nature Biotechnology 20, 1006-1010CrossRefGoogle ScholarPubMed
42Yamamoto, A., Lucas, J.J. and Hen, R. (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington's disease. Cell 101, 57-66CrossRefGoogle Scholar
43Zu, T. et al. (2004) Recovery from polyglutamine-induced neurodegeneration in conditional SCA1 transgenic mice. Journal of Neuroscience 24, 8853-8861CrossRefGoogle ScholarPubMed
44Rodriguez-Lebron, E. and Paulson, H.L. (2005) Allele-specific RNA interference for neurological disease. Gene Therapy 13, 576-581CrossRefGoogle Scholar
45Scholefield, J. and Wood, M.J.A. (2010) Therapeutic gene silencing strategies for polyglutamine disorders. Trends in Genetics 26, 29-38CrossRefGoogle ScholarPubMed
46Kubodera, T. et al. (2010) In vivo application of an RNAi strategy for the selective suppression of a mutant allele. Human Gene Therapy 22, 27-34CrossRefGoogle Scholar
47Kubodera, T. et al. (2005) New RNAi strategy for selective suppression of a mutant allele in polyglutamine disease. Oligonucleotides 15, 298-302CrossRefGoogle ScholarPubMed
48Nasir, J. et al. (1995) Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811-823CrossRefGoogle ScholarPubMed
49Dragatsis, I., Levine, M.S. and Zeitlin, S. (2000) Inactivation of hdh in the brain and testis results in progressive neurodegeneration and sterility in mice. Nature Genetics 26, 300-306CrossRefGoogle ScholarPubMed
50Van Raamsdonk, J.M. et al. (2005) Loss of wild-type huntingtin influences motor dysfunction and survival in the YAC128 mouse model of Huntington disease. Human Molecular Genetics 14, 1379-1392CrossRefGoogle ScholarPubMed
51Persichetti, F. et al. (1996) Differential expression of normal and mutant Huntington's disease gene alleles. Neurobiology of Disease 3, 183-190CrossRefGoogle ScholarPubMed
52Ambrose, C.M. et al. (1994) Structure and expression of the Huntington's disease gene: evidence against simple inactivation due to an expanded CAG repeat. Somatic Cell and Molecular Genetics 20, 27-38CrossRefGoogle Scholar
53Matilla, A. et al. (1998) Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. Journal of Neuroscience 18, 5508-5516CrossRefGoogle ScholarPubMed
54Jun, K. et al. (1999) Ablation of P/Q-type Ca2 channel currents, altered synaptic transmission, and progressive ataxia in mice lacking the α1A-subunit. Proceedings of the National Academy of Sciences of the United States of America 96, 15245-15250CrossRefGoogle Scholar
55Crespo-Barreto, J. et al. (2010) Partial loss of ataxin-1 function contributes to transcriptional dysregulation in spinocerebellar ataxia type 1 pathogenesis. PLoS Genetics 6, 575-621CrossRefGoogle ScholarPubMed
56Lim, J. et al. (2008) Opposing effects of polyglutamine expansion on native protein complexes contribute to SCA1. Nature 452, 713-718CrossRefGoogle ScholarPubMed
57Warrick, J.M. et al. (2005) Ataxin-3 suppresses polyglutamine neurodegeneration in drosophila by a ubiquitin-associated mechanism. Molecular Cell 18, 37-48CrossRefGoogle ScholarPubMed
58Schmitt, I. et al. (2007) Inactivation of the mouse Atxn3 (ataxin-3) gene increases protein ubiquitination. Biochemical and Biophysical Research Communications 362, 734-739CrossRefGoogle ScholarPubMed
59Figueroa, K.P. and Pulst, S.M. (2003) Identification and expression of the gene for human ataxin-2-related protein on chromosome 16. Experimental Neurology 184, 669-678CrossRefGoogle ScholarPubMed
60Shen, Y. et al. (2007) Functional architecture of atrophins. Journal of Biological Chemistry 282, 5037-5044CrossRefGoogle ScholarPubMed
61Rooms, L. et al. (2006) TBP as a candidate gene for mental retardation in patients with subtelomeric 6q deletions. European Journal of Human Genetics 14, 1090-1096CrossRefGoogle ScholarPubMed
62Yeh, S. et al. (2002) Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues. Proceedings of the National Academy of Sciences of the United States of America 99, 13498-13503CrossRefGoogle Scholar
63Wang, R.S. et al. (2009) Androgen receptor roles in spermatogenesis and fertility: lessons from testicular cell-specific androgen receptor knockout mice. Endocrine Reviews 30, 119-132CrossRefGoogle ScholarPubMed
64Weinberg, M.S. and Wood, M.J.A. (2009) Short non-coding RNA biology and neurodegenerative disorders: novel disease targets and therapeutics. Human Molecular Genetics 18, R27-R39CrossRefGoogle ScholarPubMed
65Zamore, P.D. et al. (2000) RNAi:: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101, 25-33CrossRefGoogle ScholarPubMed
66Castanotto, D. and Rossi, J.J. (2009) The promises and pitfalls of RNA-interference-based therapeutics. Nature 457, 426-433CrossRefGoogle ScholarPubMed
67Boudreau, R.L., Monteys, A.M. and Davidson, B.L. (2008) Minimizing variables among hairpin-based RNAi vectors reveals the potency of shRNAs. RNA 14, 1834-1844CrossRefGoogle ScholarPubMed
68Grimm, D. et al. (2006) Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways. Nature 441, 537-541CrossRefGoogle ScholarPubMed
69Boudreau, R.L., Martins, I. and Davidson, B.L. (2008) Artificial microRNAs as siRNA shuttles: improved safety as compared to shRNAs in vitro and in vivo. Molecular Therapy 17, 169-175CrossRefGoogle ScholarPubMed
70Denovan-Wright, E.M. et al. (2008) Unexpected off-targeting effects of anti-huntingtin ribozymes and siRNA in vivo. Neurobiology of Disease 29, 446-455CrossRefGoogle ScholarPubMed
71Bauer, M. et al. (2008) Prevention of interferon-stimulated gene expression using microRNA-designed hairpins. Gene Therapy 16, 142-147CrossRefGoogle ScholarPubMed
72McBride, J.L. et al. (2008) Artificial miRNAs mitigate shRNA-mediated toxicity in the brain: implications for the therapeutic development of RNAi. Proceedings of the National Academy of Sciences of the United States of America 105, 5868-5873CrossRefGoogle ScholarPubMed
73Smith, R.A. et al. (2006) Antisense oligonucleotide therapy for neurodegenerative disease. Journal of Clinical Investigation 116, 2290-2296CrossRefGoogle ScholarPubMed
74Crooke, S.T. (2004) Progress in antisense technology. Annual Review of Medicine 55, 61-95CrossRefGoogle ScholarPubMed
75Gagnon, K.T. et al. (2010) Allele-selective inhibition of mutant huntingtin expression with antisense oligonucleotides targeting the expanded CAG repeat. Biochemistry 49, 10166-10178CrossRefGoogle ScholarPubMed
76Boudreau, R.L. et al. (2009) Nonallele-specific silencing of mutant and wild-type huntingtin demonstrates therapeutic efficacy in Huntington's disease mice. Molecular Therapy 17, 1053-1063CrossRefGoogle ScholarPubMed
77Harper, S.Q. et al. (2005) RNA interference improves motor and neuropathological abnormalities in a Huntington's disease mouse model. Proceedings of the National Academy of Sciences of the United States of America 102, 5820-5825CrossRefGoogle Scholar
78Caplen, N.J. et al. (2002) Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. Human Molecular Genetics 11, 175-184CrossRefGoogle ScholarPubMed
79Xia, H. et al. (2004) RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nature Medicine 10, 816-820CrossRefGoogle Scholar
80Boado, R.J. et al. (2000) Antisense-mediated down-regulation of the human huntingtin gene. Journal of Pharmacology and Experimental Therapeutics 295, 239-243Google ScholarPubMed
81Rodriguez-Lebron, E. et al. (2005) Intrastriatal rAAV-mediated delivery of anti-huntingtin shRNAs induces partial reversal of disease progression in R6/1 Huntington's disease transgenic mice. Molecular Therapy 12, 618-633CrossRefGoogle ScholarPubMed
82Franich, N.R. et al. (2008) AAV vector–mediated RNAi of mutant huntingtin expression is neuroprotective in a novel genetic rat model of Huntington's disease. Molecular Therapy 16, 947-956CrossRefGoogle Scholar
83Machida, Y. et al. (2006) rAAV-mediated shRNA ameliorated neuropathology in Huntington disease model mouse. Biochemical and Biophysical Research Communications 343, 190-197CrossRefGoogle ScholarPubMed
84Alves, S. et al. (2010) Silencing ataxin-3 mitigates degeneration in a rat model of Machado–Joseph disease: no role for wild-type ataxin-3? Human Molecular Genetics 19, 2380-2394CrossRefGoogle Scholar
85Abdelgany, A., Wood, M. and Beeson, D. (2003) Allele-specific silencing of a pathogenic mutant acetylcholine receptor subunit by RNA interference. Human Molecular Genetics 12, 2637-2644CrossRefGoogle ScholarPubMed
86Gonzalez-Alegre, P. et al. (2003) Toward therapy for DYT1 dystonia: allele-specific silencing of mutant TorsinA. Annals of Neurology 53, 781-787CrossRefGoogle ScholarPubMed
87Xia, X. et al. (2006) Allele-specific RNAi selectively silences mutant SOD1 and achieves significant therapeutic benefit in vivo. Neurobiology of Disease 23, 578-586CrossRefGoogle ScholarPubMed
88Schwarz, D.S. et al. (2006) Designing siRNA that distinguish between genes that differ by a single nucleotide. PLoS Genetics 2, e140CrossRefGoogle ScholarPubMed
89Bilsen, P.H.J. et al. (2008) Identification and allele-specific silencing of the mutant huntingtin allele in Huntington's disease patient-derived fibroblasts. Human Gene Therapy 19, 710-718CrossRefGoogle ScholarPubMed
90Pfister, E.L. et al. (2009) Five siRNAs targeting three SNPs may provide therapy for three-quarters of Huntington's disease patients. Current Biology 19, 774-778CrossRefGoogle ScholarPubMed
91Ohnishi, Y. et al. (2008) Enhancement of allele discrimination by introduction of nucleotide mismatches into siRNA in allele-specific gene silencing by RNAi. PloS One 3, e2248CrossRefGoogle ScholarPubMed
92Lombardi, M.S. et al. (2009) A majority of Huntington's disease patients may be treatable by individualized allele-specific RNA interference. Experimental Neurology 217, 312-319CrossRefGoogle ScholarPubMed
93Zhang, Y., Engelman, J. and Friedlander, R.M. (2009) Allele-specific silencing of mutant Huntington's disease gene. Journal of Neurochemistry 108, 82-90CrossRefGoogle ScholarPubMed
94Li, Y. et al. (2004) Sequence-dependent and independent inhibition specific for mutant ataxin-3 by small interfering RNA. Annals of Neurology 56, 124-129CrossRefGoogle ScholarPubMed
95Gaspar, C. et al. (1996) Linkage disequilibrium analysis in Machado-Joseph disease patients of different ethnic origins. Human Genetics 98, 620-624CrossRefGoogle ScholarPubMed
96Miller, V.M. et al. (2003) Allele-specific silencing of dominant disease genes. Proceedings of the National Academy of Sciences of the United States of America 100, 7195-7200CrossRefGoogle ScholarPubMed
97Alves, S. et al. (2008) Allele-specific RNA silencing of mutant ataxin-3 mediates neuroprotection in a rat model of Machado-Joseph disease. PLoS One 3, e3341CrossRefGoogle Scholar
98Scholefield, J. et al. (2009) Design of RNAi hairpins for mutation-specific silencing of ataxin-7 and correction of a SCA7 phenotype. PLoS One 4, e7232CrossRefGoogle ScholarPubMed
99Cattaneo, E. et al. (2001) Loss of normal huntingtin function: new developments in Huntington's disease research. Trends in Neurosciences 24, 182-188CrossRefGoogle ScholarPubMed
100Hu, J., Matsui, M. and Corey, D.R. (2009) Allele-selective inhibition of mutant huntingtin by peptide nucleic acid-peptide conjugates, locked nucleic acid, and small interfering RNA. Annals of the New York Academy of Sciences 1175, 24-31CrossRefGoogle ScholarPubMed
101Kastelein, J.J.P. et al. (2006) Potent reduction of apolipoprotein B and low-density lipoprotein cholesterol by short-term administration of an antisense inhibitor of apolipoprotein B. Circulation 114, 1729-1735CrossRefGoogle ScholarPubMed
102Sah, D.W.Y. and Aronin, N. (2011) Oligonucleotide therapeutic approaches for Huntington disease. Journal of Clinical Investigation 121, 500-507CrossRefGoogle ScholarPubMed
103Hu, J., Liu, J. and Corey, D.R. (2010) Allele-selective inhibition of huntingtin expression by switching to an miRNA-like RNAi mechanism. Chemistry and Biology 17, 1183-1188CrossRefGoogle Scholar
104Kim, D.H. and Rossi, J.J. (2003) Coupling of RNAi-mediated target downregulation with gene replacement. Antisense and Nucleic Acid Drug Development 13, 151-155CrossRefGoogle ScholarPubMed
105Kim, D.H. et al. (2008) MicroRNA-directed transcriptional gene silencing in mammalian cells. Proceedings of the National Academy of Sciences of the United States of America 105, 16230-16235CrossRefGoogle ScholarPubMed
106Younger, S.T. and Corey, D.R. (2011) Transcriptional gene silencing in mammalian cells by miRNA mimics that target gene promoters. Nucleic Acids Research 39, 5682-5691CrossRefGoogle ScholarPubMed
107Hawkins, P.G. et al. (2009) Promoter targeted small RNAs induce long-term transcriptional gene silencing in human cells. Nucleic Acids Research 37, 2984-2995CrossRefGoogle ScholarPubMed
108Morris, K.V. et al. (2008) Bidirectional transcription directs both transcriptional gene activation and suppression in human cells. PLoS Genetics 4, e1000258CrossRefGoogle ScholarPubMed
109Han, J., Kim, D. and Morris, K.V. (2007) Promoter-associated RNA is required for RNA-directed transcriptional gene silencing in human cells. Proceedings of the National Academy of Sciences of the United States of America 104, 12422-12427CrossRefGoogle ScholarPubMed
110Li, L.B. et al. (2008) RNA toxicity is a component of ataxin-3 degeneration in drosophila. Nature 453, 1107-1111CrossRefGoogle ScholarPubMed
111de Mezer, M. et al. (2011) Mutant CAG repeats of huntingtin transcript fold into hairpins, form nuclear foci and are targets for RNA interference. Nucleic Acids Research 39, 3852-3863CrossRefGoogle ScholarPubMed
112Wheeler, T.M. et al. (2009) Reversal of RNA dominance by displacement of protein sequestered on triplet repeat RNA. Science 325, 336-339CrossRefGoogle ScholarPubMed
113Todd, P.K. and Paulson, H.L. (2010) RNA-mediated neurodegeneration in repeat expansion disorders. Annals of Neurology 67, 291-300CrossRefGoogle ScholarPubMed
114Dickson, A.M. and Wilusz, C.J. (2010) Repeat expansion diseases: when a good RNA turns bad. Wiley Interdisciplinary Reviews – RNA 1, 173-192CrossRefGoogle Scholar
115Roshan, R. et al. (2009) MicroRNAs: novel therapeutic targets in neurodegenerative diseases. Drug Discovery Today 14, 1123-1129CrossRefGoogle ScholarPubMed
116Johnson, R. et al. (2007) A microRNA-based gene dysregulation pathway in Huntington's disease. Neurobiology of Disease 29, 438-445CrossRefGoogle ScholarPubMed
117Lee, Y. et al. (2008) miR-19, miR-101 and miR-130 co-regulate ATXN1 levels to potentially modulate SCA1 pathogenesis. Nature Neuroscience 11, 1137-1139CrossRefGoogle ScholarPubMed
118Lundstrom, K. (2011) Micro-RNA in disease and gene therapy. Current Drug Discovery Technologies 8, 76-86CrossRefGoogle ScholarPubMed
119Bilen, J., Liu, N. and Bonini, N.M. (2006) A new role for microRNA pathways: modulation of degeneration induced by pathogenic human disease proteins. Cell Cycle 5, 2835-2838CrossRefGoogle ScholarPubMed
120Schaefer, A. et al. (2007) Cerebellar neurodegeneration in the absence of microRNAs. Journal of Experimental Medicine 204, 1553-1558CrossRefGoogle ScholarPubMed
121Giraldez, A.J. et al. (2005) MicroRNAs regulate brain morphogenesis in zebrafish. Science 308, 833-838CrossRefGoogle ScholarPubMed
122Lesnik, J.K. and Antes, T.J. (2010) Permanent knockdown of microRNAs using lentivectors. BioTechniques 48, 321-323CrossRefGoogle Scholar
123Lennox, K. and Behlke, M. (2011) Chemical modification and design of anti-miRNA oligonucleotides. Gene Therapy 18, 1111-1120CrossRefGoogle ScholarPubMed
124Elmén, J. et al. (2008) LNA-mediated microRNA silencing in non-human primates. Nature 452, 896-899CrossRefGoogle ScholarPubMed
125Obad, S. et al. (2011) Silencing of microRNA families by seed-targeting tiny LNAs. Nature Genetics 43, 371-378CrossRefGoogle ScholarPubMed
126Worm, J. et al. (2009) Silencing of microRNA-155 in mice during acute inflammatory response leads to derepression of c/ebp beta and down-regulation of G-CSF. Nucleic Acids Research 37, 5784-5792CrossRefGoogle ScholarPubMed
127Jadhav, V.M., Scaria, V. and Maiti, S. (2009) Antagomirzymes: oligonucleotide enzymes that specifically silence microRNA function. Angewandte Chemie International Edition 48, 2557-2560CrossRefGoogle ScholarPubMed
128Broderick, J.A. and Zamore, P.D. (2011) MicroRNA therapeutics. Gene Therapy advance online publication, 28 April 2011; doi:10.1038/gt.2011.50CrossRefGoogle Scholar
129Cao, W. et al. (2005) DNA constructs designed to produce short hairpin, interfering RNAs in transgenic mice sometimes show early lethality and an interferon response. Journal of Applied Genetics 46, 217-225Google Scholar
130Sledz, C.A. et al. (2003) Activation of the interferon system by short-interfering RNAs. Nature Cell Biology 5, 834-839CrossRefGoogle ScholarPubMed
131Jackson, A.L. and Linsley, P.S. (2010) Recognizing and avoiding siRNA off-target effects for target identification and therapeutic application. Nature Reviews Drug Discovery 9, 57-67CrossRefGoogle ScholarPubMed
132Jackson, A.L. et al. (2003) Expression profiling reveals off-target gene regulation by RNAi. Nature Biotechnology 21, 635-637CrossRefGoogle ScholarPubMed
133Jackson, A.L. et al. (2006) Widespread siRNA “off-target” transcript silencing mediated by seed region sequence complementarity. RNA 12, 1179-1187CrossRefGoogle ScholarPubMed
134Persengiev, S.P., Zhu, X. and Green, M.R. (2004) Nonspecific, concentration-dependent stimulation and repression of mammalian gene expression by small interfering RNAs (siRNAs). RNA 10, 12-18CrossRefGoogle ScholarPubMed
135Naito, Y. et al. (2004) siDirect: highly effective, target-specific siRNA design software for mammalian RNA interference. Nucleic Acids Research 32 (Suppl. 2), W124-W129CrossRefGoogle ScholarPubMed
136Kittler, R. et al. (2007) Genome-wide resources of endoribonuclease-prepared short interfering RNAs for specific loss-of-function studies. Nature Methods 4, 337-344CrossRefGoogle ScholarPubMed
137Bramsen, J.B. et al. (2010) A screen of chemical modifications identifies position-specific modification by UNA to most potently reduce siRNA off-target effects. Nucleic Acids Research 38, 5761-5773CrossRefGoogle ScholarPubMed
138Fedorov, Y. et al. (2006) Off-target effects by siRNA can induce toxic phenotype. RNA 12, 1188-1196CrossRefGoogle ScholarPubMed
139Jackson, A.L. et al. (2006) Position-specific chemical modification of siRNAs reduces “off-target” transcript silencing. RNA 12, 1197-1205CrossRefGoogle ScholarPubMed
140Hornung, V. et al. (2005) Sequence-specific potent induction of IFN-α by short interfering RNA in plasmacytoid dendritic cells through TLR7. Nature Medicine 11, 263-270CrossRefGoogle ScholarPubMed
141Judge, A.D. et al. (2006) Design of noninflammatory synthetic siRNA mediating potent gene silencing in vivo. Molecular Therapy 13, 494-505CrossRefGoogle ScholarPubMed
142Sioud, M. (2005) Induction of inflammatory cytokines and interferon responses by double-stranded and single-stranded siRNAs is sequence-dependent and requires endosomal localization. Journal of Molecular Biology 348, 1079-1090CrossRefGoogle ScholarPubMed
143Kleinman, M.E. et al. (2008) Sequence-and target-independent angiogenesis suppression by siRNA via TLR3. Nature 452, 591-597CrossRefGoogle ScholarPubMed
144Khan, A.A. et al. (2009) Transfection of small RNAs globally perturbs gene regulation by endogenous microRNAs. Nature Biotechnology 27, 549-555CrossRefGoogle ScholarPubMed
145Dessy, A. and Gorman, J.M. (2011) The emerging therapeutic role of RNA interference in disorders of the central nervous system. Clinical Pharmacology and Therapeutics 89, 450-454CrossRefGoogle ScholarPubMed
146Eberling, J.L. et al. (2008) Results from a phase I safety trial of hAADC gene therapy for Parkinson disease. Neurology 70, 1980-1983CrossRefGoogle ScholarPubMed
147Naldini, L. et al. (1996) Efficient transfer, integration, and sustained long-term expression of the transgene in adult rat brains injected with a lentiviral vector. Proceedings of the National Academy of Sciences of the United States of America 93, 11382-11388CrossRefGoogle ScholarPubMed
148Dorn, G. et al. (2004) siRNA relieves chronic neuropathic pain. Nucleic Acids Research 32, e49CrossRefGoogle ScholarPubMed
149Alvarez-Erviti, L. et al. (2011) Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology 29, 341-345CrossRefGoogle Scholar
150Agrawal, A. et al. (2009) Functional delivery of siRNA in mice using dendriworms. ACS Nano 3, 2495-2504CrossRefGoogle ScholarPubMed
151Luo, M.C. et al. (2005) An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons. Molecular Pain 1, 29-36CrossRefGoogle Scholar
152Vaishnaw, A.K. et al. (2010) A status report on RNAi therapeutics. Silence 1, 1-13CrossRefGoogle ScholarPubMed
153Cattaneo, E., Zuccato, C. and Tartari, M. (2005) Normal huntingtin function: an alternative approach to Huntington's disease. Nature Reviews Neuroscience 6, 919-930CrossRefGoogle ScholarPubMed
154Wang, L. et al. (2006) Histone deacetylase-associating atrophin proteins are nuclear receptor corepressors. Genes and Development 20, 525-530CrossRefGoogle ScholarPubMed
155Goold, R. et al. (2007) Down-regulation of the dopamine receptor D2 in mice lacking ataxin 1. Human Molecular Genetics 16, 2122-2134CrossRefGoogle ScholarPubMed
156Ralser, M. et al. (2005) An integrative approach to gain insights into the cellular function of human ataxin-2. Journal of Molecular Biology 346, 203-214CrossRefGoogle ScholarPubMed
157Kiehl, T.R. et al. (2006) Generation and characterization of Sca2 (ataxin-2) knockout mice. Biochemical and Biophysical Research Communications 339, 17-24CrossRefGoogle ScholarPubMed
158Huynh, D.P. et al. (2009) Dissociated fear and spatial learning in mice with deficiency of ataxin-2. PloS One 4, e6235CrossRefGoogle ScholarPubMed
159Evert, B.O. et al. (1999) High level expression of expanded full-length ataxin-3 in vitro causes cell death and formation of intranuclear inclusions in neuronal cells. Human Molecular Genetics 8, 1169-1176CrossRefGoogle ScholarPubMed
160Helmlinger, D. et al. (2004) Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Human Molecular Genetics 13, 1257-1265CrossRefGoogle ScholarPubMed
161Shah, A.G. et al. (2009) Transcriptional dysregulation of TrkA associates with neurodegeneration in spinocerebellar ataxia type 17. Human Molecular Genetics 18, 4141-4152CrossRefGoogle ScholarPubMed
162van Roon-Mom, W.M.C. et al. (2005) TATA-binding protein in neurodegenerative disease. Neuroscience 133, 863-872CrossRefGoogle ScholarPubMed
163Zimmermann, T.S. et al. (2006) RNAi-mediated gene silencing in non-human primates. Nature 441, 111-114CrossRefGoogle ScholarPubMed
164Henry, S. et al. (2000) Chemically modified oligonucleotides exhibit decreased immune stimulation in mice. Journal of Pharmacology and Experimental Therapeutics 292, 468-479Google ScholarPubMed
165Kunze, D., Kraemer, K. and Fuessel, S. (2010) Antisense oligonucleotides: insights from preclinical studies and clinical trials. In RNA Technologies and their Applications (Erdmann, V.A. and Barciszewski, J., eds), pp. 285-303, Springer, Berlin HeidelbergCrossRefGoogle Scholar

Further reading, resources and contacts

Di Prospero, N.A. and Fischbeck, K.H. (2005) Therapeutics development for triplet repeat expansion diseases. Nature Reviews Genetics 6, 756-767CrossRefGoogle ScholarPubMed
Kim, D.H. and Rossi, J.J. (2007) Strategies for silencing human disease using RNA interference. Nature Reviews Genetics 8, 173-184CrossRefGoogle ScholarPubMed
La Spada, A.R. and Taylor, J.P. (2010) Repeat expansion disease: progress and puzzles in disease pathogenesis. Nature Reviews Genetics 11, 247-258CrossRefGoogle ScholarPubMed
Malecová, B. and Morris, K.V. (2010) Transcriptional gene silencing mediated by non-coding RNAs. Current Opinion in Molecular Therapeutics 12, 214-222Google ScholarPubMed
Takahashi, M. et al. (2010) Tailor-made RNAi knockdown against triplet repeat disease-causing alleles. Proceedings of the National Academy of Sciences of the United States of America 107, 21731-21736CrossRefGoogle ScholarPubMed