Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic gene silencing in neurological disorders, using interfering RNA

  • Review
  • Published:
Journal of Molecular Medicine Aims and scope Submit manuscript

Abstract

The development of interfering RNA (RNAi) from a naturally occurring phenomenon to a tool for mediating highly specific gene silencing provides an exciting prospect as a novel therapeutic strategy for a wide range of disorders. Although the efficacy of RNAi as a research tool for analysing gene function has been well demonstrated in several cell types, the therapeutic potential of RNAi-mediated gene silencing has only recently started to be investigated. Several neurodegenerative disorders provide particularly suitable candidates for RNAi based therapy; however, many hurdles preclude the success of therapeutic application. These include the challenge of delivering active RNAi molecules to the specific target cell populations where they are required and appropriate regulation of gene suppression, such as to maintain a long-lasting therapeutic effect. Furthermore, for safety reasons, off-target effects should be minimised. Here we review the advancement of RNAi technology for therapeutic application and highlight the potential of targeted gene silencing for the treatment of neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Napoli C, Lemieux C, Jorgensen R (1990) Introduction of a chimeric chalcone synthase gene into petunia results in reversible co-suppression of homologous genes in trans. Plant Cell 2:279–289

    Article  CAS  PubMed  Google Scholar 

  2. van der Krol AR, Mur LA, Beld M, Mol JN, Stuitje AR (1990) Flavonoid genes in petunia: addition of a limited number of gene copies may lead to a suppression of gene expression. Plant Cell 2:291–299

    Google Scholar 

  3. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC (1998) Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391:806–811

    Article  CAS  PubMed  Google Scholar 

  4. Zamore PD, Tuschl T, Sharp PA, Bartel DP (2000) RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101:25–33

    Article  CAS  PubMed  Google Scholar 

  5. Elbashir SM, Lendeckel W, Tuschl T (2001) RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev 15:188–200

    Article  CAS  PubMed  Google Scholar 

  6. Ui-Tei K, Zenno S, Miyata Y, Saigo K (2000) Sensitive assay of RNA interference in Drosophila and Chinese hamster cultured cells using firefly luciferase gene as target. FEBS Lett 479:79–82

    Article  CAS  PubMed  Google Scholar 

  7. Caplen NJ, Fleenor J, Fire A, Morgan RA (2000) dsRNA-mediated gene silencing in cultured Drosophila cells: a tissue culture model for the analysis of RNA interference. Gene 252:95–105

    Google Scholar 

  8. Stark GR, Kerr IM, Williams BR, Silverman RH, Schreiber RD (1998) How cells respond to interferons. Annu Rev Biochem 67:227–264

    Article  CAS  PubMed  Google Scholar 

  9. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498

    Article  CAS  PubMed  Google Scholar 

  10. Xia H, Mao Q, Paulson HL, Davidson BL (2002) siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 20:1006–1010

    Google Scholar 

  11. Hasuwa H, Kaseda K, Einarsdottir T, Okabe M (2002) Small interfering RNA and gene silencing in transgenic mice and rats. FEBS Lett 532:227–230

    Google Scholar 

  12. Paul CP, Good PD, Winer I, Engelke DR (2002) Effective expression of small interfering RNA in human cells. Nat Biotechnol 20:505–508

    Google Scholar 

  13. Carmell MA, Zhang L, Conklin DS, Hannon GJ, Rosenquist TA (2003) Germline transmission of RNAi in mice. Nat Struct Biol 10:91–92

    Google Scholar 

  14. Novina CD, Sharp PA (2004) The RNAi revolution. Nature 430:161–164

    Google Scholar 

  15. Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366

    Article  CAS  PubMed  Google Scholar 

  16. Hammond SM, Bernstein E, Beach D, Hannon GJ (2000) An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature 404:293–296

    Article  CAS  PubMed  Google Scholar 

  17. Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574

    Article  CAS  PubMed  Google Scholar 

  18. Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297

    Article  Google Scholar 

  19. Krichevsky AM, Kosik KS (2002) RNAi functions in cultured mammalian neurons. Proc Natl Acad Sci USA 99:11926–11929

    Google Scholar 

  20. Blander G, de Oliveira RM, Conboy CM, Haigis M, Guarente L (2003) Superoxide dismutase 1 knock-down induces senescence in human fibroblasts. J Biol Chem 278:38966–38969

    Google Scholar 

  21. Brummelkamp TR, Bernards R, Agami R (2002) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553

    Article  CAS  PubMed  Google Scholar 

  22. Miyagishi M, Taira K (2002) U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol 20:497–500

    Google Scholar 

  23. Rubinson DA, Dillon CP, Kwiatkowski AV, et al (2003) A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 33:401–406

    Article  CAS  PubMed  Google Scholar 

  24. Barton GM, Medzhitov R (2002) Retroviral delivery of small interfering RNA into primary cells. Proc Natl Acad Sci USA 99:14943–14945

    Google Scholar 

  25. Hommel JD, Sears RM, Georgescu D, Simmons DL, DiLeone RJ (2003) Local gene knockdown in the brain using viral-mediated RNA interference. Nat Med 9:1539–1544

    Google Scholar 

  26. Tiscornia G, Singer O, Ikawa M, Verma IM (2003) A general method for gene knockdown in mice by using lentiviral vectors expressing small interfering RNA. Proc Natl Acad Sci USA 100:1844–1848

    Google Scholar 

  27. Reynolds A, Leake D, Boese Q, Scaringe S, Marshall WS, Khvorova A (2004) Rational siRNA design for RNA interference. Nat Biotechnol 22:326–330

    Google Scholar 

  28. Gong D, Ferrell JE Jr (2004) Picking a winner: new mechanistic insights into the design of effective siRNAs. Trends Biotechnol 22:451–454

    Google Scholar 

  29. Jackson AL, Bartz SR, Schelter J, et al (2003) Expression profiling reveals off-target gene regulation by RNAi. Nat Biotechnol 21:635–637

    Article  Google Scholar 

  30. Doench JG, Petersen CP, Sharp PA (2003) siRNAs can function as miRNAs. Genes Dev 17:438–442

    Google Scholar 

  31. Zeng Y, Yi R, Cullen BR (2003) MicroRNAs and small interfering RNAs can inhibit mRNA expression by similar mechanisms. Proc Natl Acad Sci USA 100:9779–9784

    Google Scholar 

  32. Saxena S, Jonsson ZO, Dutta A (2003) Small RNAs with imperfect match to endogenous mRNA repress translation. Implications for off-target activity of small inhibitory RNA in mammalian cells. J Biol Chem 278:44312–44319

    Google Scholar 

  33. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 34:263–264

    Article  CAS  PubMed  Google Scholar 

  34. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR (2003) Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 5:834–839

    Google Scholar 

  35. Moss EG, Taylor JM (2003) Small-interfering RNAs in the radar of the interferon system. Nat Cell Biol 5:771–772

    Google Scholar 

  36. Lewis DL, Hagstrom JE, Loomis AG, Wolff JA, Herweijer H (2002) Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet 32:107–108

    Article  CAS  PubMed  Google Scholar 

  37. Sorensen DR, Leirdal M, Sioud M (2003) Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J Mol Biol 327:761–766

    Article  CAS  PubMed  Google Scholar 

  38. Soutschek J, Akinc A, Bramlage B, et al (2004) Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173–178

    Google Scholar 

  39. Zhao LJ, Jian H, Zhu H (2003) Specific gene inhibition by adenovirus-mediated expression of small interfering RNA. Gene 316:137–141

    Google Scholar 

  40. Miyagishi M, Taira K (2002) Development and application of siRNA expression vector. Nucleic Acids Res Suppl:113–114

    Google Scholar 

  41. Wiznerowicz M, Trono D (2003) Conditional suppression of cellular genes: lentivirus vector-mediated drug-inducible RNA interference. J Virol 77:8957–8961

    Google Scholar 

  42. Hosono T, Mizuguchi H, Katayama K, et al (2004) Adenovirus vector-mediated doxycycline-inducible RNA interference. Hum Gene Ther 15:813–819

    Google Scholar 

  43. Martin-Rendon E, Azzouz M, Mazarakis ND (2001) Lentiviral vectors for the treatment of neurodegenerative diseases. Curr Opin Mol Ther 3:476–481

    Google Scholar 

  44. Blomer U, Ganser A, Scherr M (2002) Invasive drug delivery. Adv Exp Med Biol 513:431–451

    Google Scholar 

  45. Rosen DR, Siddique T, Patterson D, et al (1993) Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 362:59–62

    Article  CAS  PubMed  Google Scholar 

  46. Deng HX, Hentati A, Tainer JA, et al (1993) Amyotrophic lateral sclerosis and structural defects in Cu, Zn superoxide dismutase. Science 261:1047–1051

    CAS  PubMed  Google Scholar 

  47. Gurney ME, Pu H, Chiu AY, et al (1994) Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 264:1772–1775

    CAS  PubMed  Google Scholar 

  48. Ding H, Schwarz DS, Keene A, et al (2003) Selective silencing by RNAi of a dominant allele that causes amyotrophic lateral sclerosis. Aging Cell 2:209–217

    Google Scholar 

  49. Maxwell MM, Pasinelli P, Kazantsev AG, Brown RH Jr (2004) RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cells. Proc Natl Acad Sci USA 101:3178–3183

    Google Scholar 

  50. Bruijn LI, Becher MW, Lee MK, et al (1997) ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. Neuron 18:327–338

    Google Scholar 

  51. Wong PC, Pardo CA, Borchelt DR, et al (1995) An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 14:1105–1116

    Article  CAS  PubMed  Google Scholar 

  52. Kaspar BK, Llado J, Sherkat N, Rothstein JD, Gage FH (2003) Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 301:839–842

    Google Scholar 

  53. Azzouz M, Ralph GS, Storkebaum E, et al (2004) VEGF delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 429:413–417

    Article  CAS  PubMed  Google Scholar 

  54. Michalik A, Van Broeckhoven C (2003) Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 12 Spec No 2:R173–R186

    Google Scholar 

  55. Young AB (2003) Huntingtin in health and disease. J Clin Invest 111:299–302

    Google Scholar 

  56. Yamamoto A, Lucas JJ, Hen R (2000) Reversal of neuropathology and motor dysfunction in a conditional model of Huntington’s disease. Cell 101:57–66

    Article  CAS  PubMed  Google Scholar 

  57. Caplen NJ, Taylor JP, Statham VS, Tanaka F, Fire A, Morgan RA (2002) Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference. Hum Mol Genet 11:175–184

    Article  CAS  PubMed  Google Scholar 

  58. Miller VM, Xia H, Marrs GL, et al (2003) Allele-specific silencing of dominant disease genes. Proc Natl Acad Sci USA 100:7195–7200

    Google Scholar 

  59. Orr HT, Chung MY, Banfi S, et al (1993) Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1. Nat Genet 4:221–226

    Article  CAS  PubMed  Google Scholar 

  60. Xia H, Mao Q, Eliason SL, et al (2004) RNAi suppresses polyglutamine-induced neurodegeneration in a model of spinocerebellar ataxia. Nat Med 10:1006–1010

    Google Scholar 

  61. Okada T, Nomoto T, Shimazaki K, et al (2002) Adeno-associated virus vectors for gene transfer to the brain. Methods 28:237–247

    Google Scholar 

  62. Azzouz M, Kingsman SM, Mazarakis ND (2004) Lentiviral vectors for treating and modeling human CNS disorders. J Gene Med 6:951–962

    Google Scholar 

  63. Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997) Alpha-synuclein in Lewy bodies. Nature 388:839–840

    Article  CAS  PubMed  Google Scholar 

  64. Vila M, Przedborski S (2004) Genetic clues to the pathogenesis of Parkinson’s disease. Nat Med 10[Suppl]:S58–S62

    Google Scholar 

  65. Paisan-Ruiz C, Jain S, Evans EW, et al (2004) Cloning of the gene containing mutations that cause PARK8-linked Parkinson’s Disease. Neuron 44:595–600

    Google Scholar 

  66. Zimprich A, Biskup S, Leitner P, et al (2004) Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology. Neuron 44:601–607

    Google Scholar 

  67. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356

    Article  CAS  PubMed  Google Scholar 

  68. Miller VM, Gouvion CM, Davidson BL, Paulson HL (2004) Targeting Alzheimer’s disease genes with RNA interference: an efficient strategy for silencing mutant alleles. Nucleic Acids Res 32:661–668

    Google Scholar 

  69. Lewis J, Dickson DW, Lin WL, et al (2001) Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 293:1487–1491

    Article  CAS  PubMed  Google Scholar 

  70. Oddo S, Caccamo A, Shepherd JD, et al (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron 39:409–421

    Article  CAS  PubMed  Google Scholar 

  71. Kao SC, Krichevsky AM, Kosik KS, Tsai LH (2004) BACE1 suppression by RNA interference in primary cortical neurons. J Biol Chem 279:1942–1949

    Google Scholar 

  72. Yan R, Bienkowski MJ, Shuck ME, et al (1999) Membrane-anchored aspartyl protease with Alzheimer’s disease beta-secretase activity. Nature 402:533–537

    Google Scholar 

  73. Vassar R, Bennett BD, Babu-Khan S, et al (1999) Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286:735–741

    Google Scholar 

  74. Sisodia SS, St George-Hyslop PH (2002) Gamma-Secretase, Notch, Abeta and Alzheimer’s disease: where do the presenilins fit in? Nat Rev Neurosci 3:281–290

    Google Scholar 

  75. Wong GT, Manfra D, Poulet FM, et al (2004) Chronic treatment with the gamma-secretase inhibitor LY-411,575 inhibits beta-amyloid peptide production and alters lymphopoiesis and intestinal cell differentiation. J Biol Chem 279:12876–12882

    Google Scholar 

  76. Roberds SL, Anderson J, Basi G, et al (2001) BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer’s disease therapeutics. Hum Mol Genet 10:1317–1324

    Google Scholar 

  77. Ohm TG, Glockner F, Distl R, Treiber-Held S, Meske V, Schonheit B (2003) Plasticity and the spread of Alzheimer’s disease-like changes. Neurochem Res 28:1715–1723

    Google Scholar 

  78. Dawson HN, Ferreira A, Eyster MV, Ghoshal N, Binder LI, Vitek MP (2001) Inhibition of neuronal maturation in primary hippocampal neurons from tau deficient mice. J Cell Sci 114:1179–1187

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Oxford Biomedica, Ltd., Medawar Centre, Robert Robinson Avenue, Oxford Science Park, OX4 4GA, Oxford, UK

    G. Scott Ralph, Nicholas D. Mazarakis & Mimoun Azzouz

Authors
  1. G. Scott Ralph
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas D. Mazarakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mimoun Azzouz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mimoun Azzouz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ralph, G.S., Mazarakis, N.D. & Azzouz, M. Therapeutic gene silencing in neurological disorders, using interfering RNA. J Mol Med 83, 413–419 (2005). https://doi.org/10.1007/s00109-005-0649-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00109-005-0649-1

Keywords

Search

Navigation