Advertisement

Applied Microbiology and Biotechnology

, Volume 65, Issue 6, pp 649–657 | Cite as

RNA interference: potential therapeutic targets

  • S. Jana
  • C. Chakraborty
  • S. Nandi
  • J. K. Deb
Mini-Review

Abstract

One of the most exciting findings in recent years has been the discovery of RNA interference (RNAi). RNAi methodologies hold the promise to selectively inhibit gene expression in mammals. RNAi is an innate cellular process activated when a double-stranded RNA (dsRNA) molecule of greater than 19 duplex nucleotides enters the cell, causing the degradation of not only the invading dsRNA molecule, but also single-stranded (ssRNAs) RNAs of identical sequences, including endogenous mRNAs. The use of RNAi for genetic-based therapies has been widely studied, especially in viral infections, cancers, and inherited genetic disorders. As such, RNAi technology is a potentially useful method to develop highly specific dsRNA-based gene-silencing therapeutics.

Keywords

Generalize Dystonia Congenital Myasthenic Syndrome dsRNA Molecule siRNA Vector Nucleic Acid Delivery 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. Abdelgany AV, Wood MJA, Beeson D (2003) Allele-specific gene silencing of a pathogenic mutant acetylcholine receptor subunit by RNA interference. Hum Mol Genet 12:2637–2644CrossRefPubMedGoogle Scholar
  2. Agami R (2002) RNAi and related mechanisms and their potential use for therapy. Curr Opin Chem Biol 6:829–834CrossRefPubMedGoogle Scholar
  3. Agrawal N, Malhotra P, Bhatnagar RK (2004) siRNA-directed silencing of transgene expressed in cultured insect cells. Biochem Biophys Res Commun 320:428–434CrossRefPubMedGoogle Scholar
  4. Ahlquist P (2002) RNA-dependent RNA polymerases, viruses, and RNA silencing. Science 296:1270–1273CrossRefPubMedGoogle Scholar
  5. Barton GM, Medzhitov R (2002) Retroviral delivery of small interfering RNA into primary cells. Proc Natl Acad Sci USA 99:14943–14945CrossRefPubMedGoogle Scholar
  6. Bass BL (2001) RNA interference. The short answer. Nature 411:428–429CrossRefPubMedGoogle Scholar
  7. Bernstein E, Caudy AA, Hammond SM, Hannon GJ (2001) Role for a bidentate ribonuclease in the initiation step of RNA interference. Nature 409:363–366CrossRefPubMedGoogle Scholar
  8. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R (2003) Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 34:263–264CrossRefPubMedGoogle Scholar
  9. Brummelkamp TR, Bernards R, Agami R (2002a) A system for stable expression of short interfering RNAs in mammalian cells. Science 296:550–553Google Scholar
  10. Brummelkamp TR, Bernards R, Agami R (2002b) Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2:243–247CrossRefPubMedGoogle Scholar
  11. Caplen NJ (2002) A new approach to the inhibition of gene expression. Trends Biotechnol 20:49–51CrossRefPubMedGoogle Scholar
  12. Caplen NJ, Parrish S, Imani F, Fire A, Morgan RA (2001) Specific inhibition of gene expression by small double-stranded RNAs in invertebrate and vertebrate systems. Proc Natl Acad Sci USA 98:9742–9747CrossRefPubMedGoogle Scholar
  13. 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 11:175–184CrossRefPubMedGoogle Scholar
  14. Cerutti H (2003) RNA interference: traveling in the cell and gaining functions? Trends Genet 19:39–46CrossRefPubMedGoogle Scholar
  15. Davidson BL, Paulson HL (2004) Molecular medicine for the brain: silencing of disease genes with RNA interference. Lancet Neurol 3:145–149CrossRefPubMedGoogle Scholar
  16. Denli AM, Hannon GJ (2003) RNAi: an ever-growing puzzle. Trends Biochem Sci 28:196–201CrossRefPubMedGoogle Scholar
  17. Dillin A (2003) The specifics of small interfering RNA specificity, Proc Natl Acad Sci USA 100:6289–6291CrossRefPubMedGoogle Scholar
  18. Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K, Tuschl T (2001a) Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411:494–498CrossRefPubMedGoogle Scholar
  19. Elbashir SM, Lendeckel W, Tuschl T (2001b) RNA interference is mediated by 21- and 22-nucleotide RNAs. Genes Dev 15:188–200CrossRefPubMedGoogle Scholar
  20. Elbashir SM, Martinez J, Patkaniowska A, Lendeckel W, Tuschl T (2001c) Functional anatomy of siRNAs for mediating efficient RNAi in Drosophila melanogaster embryo lysate. EMBO J 20:6877–6888CrossRefPubMedGoogle Scholar
  21. 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 391:806–811CrossRefPubMedGoogle Scholar
  22. Gil J, Esteban M (2000) Induction of apoptosis by the dsRNAdependent protein kinase (PKR): mechanism of action. Apoptosis 5:107–114CrossRefPubMedGoogle Scholar
  23. Gitlin L, Karelsky S, Andino R (2002) Short interfering RNA confers intracellular antiviral immunity in human cells. Nature 418:430–434CrossRefPubMedGoogle Scholar
  24. Gonzalez-Alegre P, Miller VM, Davidson BL, Paulson HL (2003) Toward therapy for DYT1 dystonia: allele-specific silencing of mutant. Ann Neurol 53:781–787CrossRefPubMedGoogle Scholar
  25. Grunweller A, Wyszko E, Bieber B, Jahnel R, Erdmann VA, Kurreck J (2003) Comparison of different antisense strategies in mammalian cells using locked nucleic acids, 2V-O-methyl RNA, phosphorothioates and small interfering RNA. Nucleic Acids Res 31:3185–3193CrossRefPubMedGoogle Scholar
  26. Guo S, Kemphues KJ (1995) Par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell 81:611–620CrossRefPubMedGoogle Scholar
  27. Hagstrom JE (2000) Self-assembling complexes for in vivo gene delivery. Curr Opin Mol Ther 2:143–149PubMedGoogle Scholar
  28. Hammond SM, Bernstein E, Beach D, Hannon GJ (2000) An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophilia cells. Nature 404:293–296CrossRefPubMedGoogle Scholar
  29. Hammond SM, Boettcher S, Caudy AA, Kobayashi R, Hannon GJ (2001) Argonaute2, a link between genetic and biochemical analyses of RNAi. Science 293:1146–1150CrossRefPubMedGoogle Scholar
  30. Hannon GJ (2002) RNA interference. Nature 418:244–251CrossRefPubMedGoogle Scholar
  31. Harborth J, Elbashir SM, Bechert K, Tuschl T, Weber K (2001) Identification of essential genes in cultured mammalian cells using small interfering RNAs. J Cell Sci 114:4557–4565PubMedGoogle Scholar
  32. Holen T, Mobbs CV (2004) Lobotomy of genes: use of RNA interference in neuroscience. Neuroscience 126:1–7CrossRefPubMedGoogle Scholar
  33. Hough SR, Wiederholt KA, Burrier AC, Woolf TM, Taylor MF (2003) Why RNAi makes sense. Nat Biotechnol 21:731–732CrossRefPubMedGoogle Scholar
  34. Hutvagner G, Zamore PD (2002) RNAi: nature abhors a double-strand. Curr Opin Genet Dev 12:225–232CrossRefPubMedGoogle Scholar
  35. Hutvagner G, McLachlan J, Pasquinelli AE, Balint E, Tuschl T, Zamore PD (2001) A cellular function for the RNA-interference enzyme Dicer in the maturation of the let-7 small temporal RNA. Science 293:834–838CrossRefPubMedGoogle Scholar
  36. Jacque JM, Triques K, Stevenson M (2002) Modulation of HIV-1 replication by RNA interference. Nature 418:435–438CrossRefPubMedGoogle Scholar
  37. Jain KK (2004) RNAi and siRNA in target validation. Drug Discov Today 9:307–309CrossRefPubMedGoogle Scholar
  38. Johnson L, Greenbaum D, Cichowski K, Mercer K, Murphy E, Schmitt E et al (1997) K-ras is an essential gene in the mouse with partial functional overlap with N-ras. Genes Dev 11:2468–2481PubMedGoogle Scholar
  39. Johnson-Saliba M, Jans DA (2001) Gene therapy: optimising DNA delivery to the nucleus. Curr Drug Targets 2:371–399PubMedGoogle Scholar
  40. Kennerdell JR, Carthew RW (2000) Heritable gene silencing in Drosophila using double-stranded RNA. Nat Biotechnol 18:896–898CrossRefPubMedGoogle Scholar
  41. Ketting RF, Plasterk RH (2000) A genetic link between co-suppression and RNA interference in C. elegans. Nature 404:296–298CrossRefPubMedGoogle Scholar
  42. Ketting RF, Haverkamp TH, van Luenen HG, Plasterk RH (1999) Mut-7 of C. elegans, required for transposon silencing and RNA interference, is a homolog of Werner syndrome helicase and RnaseD. Cell 99:133–141CrossRefPubMedGoogle Scholar
  43. Ketting RF, Fischer SE, Bernstein E, Sijen T, Hannon GJ, Plasterk RH (2001) Dicer functions in RNA interference and in synthesis of small RNA involved in developmental timing in C. elegans. Genes Dev 15:2654–2659CrossRefPubMedGoogle Scholar
  44. Kim VN (2003) RNA interference in functional genomics and medicine. J Korean Med Sci 18:309–318PubMedGoogle Scholar
  45. Knight SW, Baas BL (2001) A role for the RNase III enzyme DCR-1 in RNA interference and germ line development in Caenorhabditis elegans. Science 293:2269–2271CrossRefPubMedGoogle Scholar
  46. Korea K, Nakamura K, Nakao K, Miyoshi J, Toyoshima K, Hatta T et al (1997) K-ras is essential for the development of the mouse embryo. Oncogene 15:1151–1159CrossRefPubMedGoogle Scholar
  47. Krichevsky AM, Kosik KS (2002) RNAi functions in cultured mammalian neurons. Proc Natl Acad Sci USA 99:11926–11929CrossRefPubMedGoogle Scholar
  48. Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T (2002) Identification of tissue-specific micro RNAs from mouse. Curr Biol 12:735–739CrossRefPubMedGoogle Scholar
  49. Lai EC (2002) Micro RNAs are complementary to 3′?UTR sequence motifs that mediate negative post-transcriptional regulation. Nat Genet 30:363–364CrossRefPubMedGoogle Scholar
  50. Lau NC, Lim LP, Weinstein EG, Bartel DP (2001) An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 294:858–862CrossRefPubMedGoogle Scholar
  51. Lee RC, Ambros V (2001) An extensive class of small RNAs in Caenorhabditis elegans. Science 294:862–864CrossRefPubMedGoogle Scholar
  52. Lee NS, Rossi JJ (2004) Control of HIV-1 replication by RNA interference. Virus Res 102:53–58CrossRefPubMedGoogle Scholar
  53. Lee RC, Feinbaum RL, Ambros V (1993) The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75:843–854CrossRefPubMedGoogle Scholar
  54. Lee JA, Kim HK, Kim KH, Han JH, Lee JS, Lim CS, Chang D, Kubo T, Kaang BK (2001) Overexpression of and RNA interference with the CCAAT enhancer-binding protein on long-term facilitation of Aplysia sensory to motor synapses. Learn Mem 8:220–226CrossRefPubMedGoogle Scholar
  55. Lee NS, Dohjima T, Bauer G, Li H, Li MJ, Ehsani A, Salvaterra P, Rossi J (2002) Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells. Nat Biotechnol 20:500–505PubMedGoogle Scholar
  56. 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 32:107–108CrossRefPubMedGoogle Scholar
  57. Lieberman J, Song E, Lee SK, Shankar P (2003) Interfering with disease: opportunities and roadblocks to harnessing RNA interference. Trends Mol Med 9:397–403CrossRefPubMedGoogle Scholar
  58. Mand MT, Plasterk RHA (2004) Dicer at RISC: the mechanism of RNAi. Cell 117:1–3PubMedGoogle Scholar
  59. Martinez J, Patkaniowska A, Urlaub H, Luhrmann R, Tuschl T (2002) Single-stranded antisense siRNAs guide target RNA cleavage in RNAi. Cell 110:563–574CrossRefPubMedGoogle Scholar
  60. Matsukura S, Jones PA, Takai D (2003) Establishment of conditional vectors for hairpin siRNA knockdowns. Nucleic Acids Res 31:e77CrossRefPubMedGoogle Scholar
  61. McCaffrey AP, Meuse L, Pham TT, Conklin DS, Hannon GJ, Kay MA (2002) RNA interference in adult mice. Nature 418:38–39CrossRefPubMedGoogle Scholar
  62. Miller VM, Xia H, Marrs GL, Gouvion CM, Lee G, Davidson BL, Paulson HL (2003) Allele-specific silencing of dominant disease genes. Proc Natl Acad Sci USA 100:7195–7200CrossRefPubMedGoogle Scholar
  63. Miyagishi M, Taira K (2002) U6 promoter-driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells. Nat Biotechnol 19:497–500CrossRefGoogle Scholar
  64. Moss EG (2003) Silencing unhealthy alleles naturally. Trends Biotechnol 21:185–187CrossRefPubMedGoogle Scholar
  65. Nadine L, Vastenhouw, Plasterk RHA (2004) RNAi protects the Caenorhabditis elegans germline against transposition. Trends Genet 20:314–319CrossRefPubMedGoogle Scholar
  66. Napoli C, Lemieux C, Jorgensen R (1990) Introduction of a chimeric chalcone synthase gene into petunia results in reversible cosuppression of homologous genes in trans. Plant Cell 2:279–289CrossRefPubMedGoogle Scholar
  67. Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee SK, Collman RG, Lieberman J, Shankar P, Sharp PA (2002) siRNA-directed inhibition of HIV-1 infection. Nat Med 8:681–686PubMedGoogle Scholar
  68. Omi K, Tokunaga K, Hohjoh H (2004) Long lasting RNAi activity in mammalian neurons. FEBS Lett 558:89–95CrossRefPubMedGoogle Scholar
  69. Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS (2002) Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev 16:948–958CrossRefPubMedGoogle Scholar
  70. Pal-Bhadra M, Bhadra U, Birchler JA (2002) RNAi related mechanisms affect both transcriptional and posttranscriptional transgene silencing in Drosophila. Mol Cell 9:315–327CrossRefPubMedGoogle Scholar
  71. Parrish S, Fire A (2001) Distinct roles for RDE-1 and RDE-4 during RNA interference in Caenorhabditis elegans. RNA 7:1397–1402PubMedGoogle Scholar
  72. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G (2000) The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 403:901–906CrossRefPubMedGoogle Scholar
  73. Rubinson DA, Dillon CP, Kwiatkowski AV, Sievers C, Yang L, Kopinja J, Zhang M, McManus MT, Gertler FB, Scott ML, Van Parijs L (2003) A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference. Nat Genet 33:401–406CrossRefPubMedGoogle Scholar
  74. Schütze N (2004) siRNA technology. Mol Cell Endocrinol 213:115–119CrossRefPubMedGoogle Scholar
  75. Senthil K, Radhakrishnan M, Thomas J, Gartel AL (2004) RNA interference as a new strategy against viral hepatitis. Virology 323:173–181CrossRefPubMedGoogle Scholar
  76. Sharp PA (2001) RNA interference—2001. Genes Dev 15:485–490CrossRefPubMedGoogle Scholar
  77. Shuey DJ, McMallus DE, Giordano T (2002) RNAi: gene-silencing in therapeutic intervention. Drug Discov Today 7:1040–1046CrossRefPubMedGoogle Scholar
  78. Sorensen DR, Leirdal M, Sioud M (2003) Gene silencing by systemic delivery of synthetic siRNAs in adult mice. J Mol Biol 327:761–766CrossRefPubMedGoogle Scholar
  79. Stein P, Svoboda P, Anger M, Schultz RM (2003) RNAi: mammalian oocytes do it without RNA-dependent RNA polymerase. RNA 9:187–192CrossRefPubMedGoogle Scholar
  80. Sui G, Soohoo C, Affar EB, Gay F, Shi Y, Forrester WC (2002) A DNA vector-based RNAi technology to suppress gene expression in mammalian cells. Proc Natl Acad Sci USA 99:5515–5520CrossRefPubMedGoogle Scholar
  81. Tabara H, Grishok A, Mello CC (1998) RNAi in C. elegans: soaking in the genome sequence. Science 282:430–431CrossRefPubMedGoogle Scholar
  82. Tabara H, Sarkissian M, Kelly WG, Fleenor J, Grishok A, Timmons L, Fire A, Mello CC (1999) The rde-1 gene, RNA interference, and transposon silencing in C. elegans. Cell 99:123–132CrossRefPubMedGoogle Scholar
  83. 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 100:1844–1848CrossRefPubMedGoogle Scholar
  84. Ui-Tei K, Zenno S, Miyata Y, Saigo K (2000) Sensitive assay of RNA interfernce in Drosophila and Chinese hamster cultured cells using firefly luciferase gene as target. FEBS Lett 479:79–82CrossRefPubMedGoogle Scholar
  85. Wianny F, Zernicka-Goetz M (2000) Specific interference with gene function by double-stranded RNA in early mouse development. Nat Cell Boil 2:70–75CrossRefGoogle Scholar
  86. Winston WM, Molodowitch C, Hunter CP (2002) Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 95:2456–2459CrossRefGoogle Scholar
  87. Wood MJ, Trulzsch B, Abdelgany A, Beeson D (2003) Therapeutic gene silencing in the nervous system. Hum Mol Genet 12:R279–R284CrossRefPubMedGoogle Scholar
  88. Xia H, Mao Q, Paulson HL, Davidson BL (2002) siRNA-mediated gene silencing in vitro and in vivo. Nat Biotechnol 20:1006–1010CrossRefPubMedGoogle Scholar
  89. Yu JY, DeRuiter SL, Turner DL (2002) RNA interference by expression of short interfering RNAs and hairpin RNAs in mammalian cells. Proc Natl Acad Sci USA 99:6047–6052CrossRefPubMedGoogle Scholar
  90. Zamore PD, Tuschl T, Sharp PA, Bartel DP (2000) RNAi: doublestranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals. Cell 101:25–33CrossRefPubMedGoogle Scholar
  91. Zender L, Hutker S, Liedtke C, Flemming P, Malek NP, Trautwein C, Manns MP, Kuhnel F, Kubicka S (2003) Caspase 8 small interfering RNA prevents acute liver failure in mice. Proc Natl Acad Sci USA 100:7797–7802CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2004

Authors and Affiliations

  1. 1.Department of Biochemical Engineering and BiotechnologyIndian Institute of Technology—DelhiNew DelhiIndia
  2. 2.Department of BiotechnologyInstitute of Applied medicines and researchGhaziabadIndia

Personalised recommendations