SHORT INTEFERING RNA (siRNA) AS A NOVEL THERAPEUTIC

1 RNA interference (RNAi) is a robust method of post‐transcriptional silencing of genes using double‐stranded RNA (dsRNA) with sequence homology driven specificity. The dsRNA can be between 21 and 23 nucleotides long: this is converted to small interfering RNA (siRNA), which then mediates gene silencing by degradation/blocking of translation of the target mRNA. 2 RNA interference provides a simple, fast and cost‐effective alternative to existing gene targeting approaches both in vitro and in vivo. The discovery of siRNAs that cause RNAi in mammalian cells opened the door to the therapeutic use of siRNAs. Highly intense research efforts are now aimed at developing siRNAs for therapeutic purposes. 3 Recent advances in the design and delivery of targeting molecules now allow efficient and highly specific gene silencing in mammalian systems. Synthetic siRNA libraries targeting thousands of mammalian genes are publicly available for high‐throughput genetic screens for target discovery and validation. Recent studies have demonstrated the clinical potential of aptly designed siRNAs in various types of viral infections, cancer and renal and neurodegenerative disorders. 4 The present review provides insight into the novel therapeutic strategies of siRNA technology, which is the latest development in nucleic acid‐based tools for knocking down gene expression, and its potential for silencing genes associated with various human diseases.

[1]  R. Scheule,et al.  Transient siRNA-mediated attenuation of liver expression from an alpha-galactosidase A plasmid reduces subsequent humoral immune responses to the transgene product in mice. , 2005, Molecular therapy : the journal of the American Society of Gene Therapy.

[2]  Judy Lieberman,et al.  Antibody mediated in vivo delivery of small interfering RNAs via cell-surface receptors , 2005, Nature Biotechnology.

[3]  Anne E Carpenter,et al.  Cell microarrays and RNA interference chip away at gene function , 2005, Nature Genetics.

[4]  L. Greensmith,et al.  Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model , 2005, Nature Medicine.

[5]  C. Henderson,et al.  Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS , 2005, Nature Medicine.

[6]  J Teissié,et al.  Inhibition of gene expression in mice muscle by in vivo electrically mediated siRNA delivery , 2005, Gene Therapy.

[7]  Raymond M Schiffelers,et al.  Inhibition of ocular angiogenesis by siRNA targeting vascular endothelial growth factor pathway genes: therapeutic strategy for herpetic stromal keratitis. , 2004, The American journal of pathology.

[8]  J. Clayton.  RNA interference: The silent treatment , 2004, Nature.

[9]  G. Hannon,et al.  Unlocking the potential of the human genome with RNA interference , 2004, Nature.

[10]  J. Contreras,et al.  Caspase-8 and caspase-3 small interfering RNA decreases ischemia/reperfusion injury to the liver in mice. , 2004, Surgery.

[11]  Phillip A. Sharp,et al.  The RNAi revolution , 2004, Nature.

[12]  J. G. Patton,et al.  GH1 splicing is regulated by multiple enhancers whose mutation produces a dominant-negative GH isoform that can be degraded by allele-specific small interfering RNA (siRNA). , 2004, Endocrinology.

[13]  Thomas Tuschl,et al.  siRNAs: applications in functional genomics and potential as therapeutics , 2004, Nature Reviews Drug Discovery.

[14]  Patty J. Lee,et al.  Small Interfering RNA Targeting Heme Oxygenase-1 Enhances Ischemia-Reperfusion-induced Lung Apoptosis* , 2004, Journal of Biological Chemistry.

[15]  Artemis G Hatzigeorgiou,et al.  miRNP:mRNA association in polyribosomes in a human neuronal cell line. , 2004, RNA.

[16]  D. Bartel.  MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[17]  L. Tsai,et al.  BACE1 Suppression by RNA Interference in Primary Cortical Neurons* , 2004, Journal of Biological Chemistry.

[18]  Gary Ruvkun,et al.  Identification of many microRNAs that copurify with polyribosomes in mammalian neurons , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  C. Cepko,et al.  Electroporation and RNA interference in the rodent retina in vivo and in vitro , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[20]  F. Leenders,et al.  Inducible shRNA expression for application in a prostate cancer mouse model. , 2003, Nucleic acids research.

[21]  Yang Shi,et al.  Small RNA: can RNA interference be exploited for therapy? , 2003, The Lancet.

[22]  M. Wood,et al.  Therapeutic gene silencing in the nervous system. , 2003, Human molecular genetics.

[23]  R. Ray,et al.  Inhibition of hepatitis C virus protein expression by RNA interference. , 2003, Virus research.

[24]  C. Wahlestedt,et al.  Lack of efficacy of 'naked' small interfering RNA applied directly to rat brain. , 2003, Acta physiologica Scandinavica.

[25]  T. Rana,et al.  siRNA function in RNAi: a chemical modification analysis. , 2003, RNA.

[26]  Judy Lieberman,et al.  Interfering with disease: opportunities and roadblocks to harnessing RNA interference , 2003, Trends in Molecular Medicine.

[27]  F. Buchholz,et al.  RNA interference: gene silencing in the fast lane. , 2003, Seminars in cancer biology.

[28]  V. Ambros,et al.  Role of MicroRNAs in Plant and Animal Development , 2003, Science.

[29]  David R Corey,et al.  RNA interference in mammalian cells by chemically-modified RNA. , 2003, Biochemistry.

[30]  M. Manns,et al.  Caspase 8 small interfering RNA prevents acute liver failure in mice , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Haibin Xia,et al.  Allele-specific silencing of dominant disease genes , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[32]  H. Paulson,et al.  Toward therapy for DYT1 dystonia: Allele‐specific silencing of mutant TorsinA , 2003, Annals of neurology.

[33]  A. Klippel,et al.  Structural variations and stabilising modifications of synthetic siRNAs in mammalian cells. , 2003, Nucleic acids research.

[34]  M. Woodle,et al.  siRNA-mediated antitumorigenesis for drug target validation and therapeutics. , 2003, Current opinion in molecular therapeutics.

[35]  J. Bennett,et al.  Small interfering RNA (siRNA) targeting VEGF effectively inhibits ocular neovascularization in a mouse model. , 2003, Molecular vision.

[36]  K. Eguchi,et al.  Short interfering RNA‐directed inhibition of hepatitis B virus replication , 2003, FEBS letters.

[37]  Mouldy Sioud,et al.  Gene silencing by systemic delivery of synthetic siRNAs in adult mice. , 2003, Journal of molecular biology.

[38]  Y. Guan,et al.  Prophylactic and Therapeutic Effects of Small Interfering Rna Targeting Sars-Coronavirus , 2003, Antiviral therapy.

[39]  Judy Lieberman,et al.  RNA interference targeting Fas protects mice from fulminant hepatitis , 2003, Nature Medicine.

[40]  Anastasia Khvorova,et al.  RNA interference blocks gene expression and RNA synthesis from hepatitis C replicons propagated in human liver cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[41]  Michael T. McManus,et al.  RNA interference of influenza virus production by directly targeting mRNA for degradation and indirectly inhibiting all viral RNA transcription , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[42]  F. Chisari,et al.  Interference of hepatitis C virus RNA replication by short interfering RNAs , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[43]  K. Taira,et al.  Comparison of the suppressive effects of antisense oligonucleotides and siRNAs directed against the same targets in mammalian cells. , 2003, Antisense & nucleic acid drug development.

[44]  K. Kiyosawa,et al.  RNA interference is a functional pathway with therapeutic potential in human myeloid leukemia cell lines , 2003, Cancer Gene Therapy.

[45]  M. Amarzguioui,et al.  Tolerance for mutations and chemical modifications in a siRNA. , 2003, Nucleic acids research.

[46]  R. Warren,et al.  Intravascular adenoviral agents in cancer patients: Lessons from clinical trials , 2002, Cancer Gene Therapy.

[47]  W. Huttner,et al.  Tissue-specific RNA interference in postimplantation mouse embryos with endoribonuclease-prepared short interfering RNA , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[48]  Haibin Xia,et al.  siRNA-mediated gene silencing in vitro and in vivo , 2002, Nature Biotechnology.

[49]  J. Milner,et al.  Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference , 2002, Oncogene.

[50]  V. Kim,et al.  MicroRNA maturation: stepwise processing and subcellular localization , 2002, The EMBO journal.

[51]  T. Rana,et al.  RNAi in human cells: basic structural and functional features of small interfering RNA. , 2002, Molecular cell.

[52]  R. Bernards,et al.  Stable suppression of tumorigenicity by virus-mediated RNA interference. , 2002, Cancer cell.

[53]  David L. Lewis,et al.  Efficient delivery of siRNA for inhibition of gene expression in postnatal mice , 2002, Nature Genetics.

[54]  P. Opolon,et al.  Comparison of antisense oligonucleotides and siRNAs in cell culture and in vivo. , 2002, Biochemical and biophysical research communications.

[55]  A. Borkhardt,et al.  Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi) , 2002, Oncogene.

[56]  R. Andino,et al.  Short interfering RNA confers intracellular antiviral immunity in human cells , 2002, Nature.

[57]  J. Lieberman,et al.  siRNA-directed inhibition of HIV-1 infection , 2002, Nature Medicine.

[58]  Paul Ahlquist,et al.  RNA-Dependent RNA Polymerases, Viruses, and RNA Silencing , 2002, Science.

[59]  Ali Ehsani,et al.  Expression of small interfering RNAs targeted against HIV-1 rev transcripts in human cells , 2002, Nature Biotechnology.

[60]  Yuan Zhou,et al.  Post-transcriptional suppression of gene expression in Xenopus embryos by small interfering RNA. , 2002, Nucleic acids research.

[61]  Phillip D Zamore,et al.  RNAi: nature abhors a double-strand. , 2002, Current opinion in genetics & development.

[62]  Craig P. Hunter,et al.  Systemic RNAi in C. elegans Requires the Putative Transmembrane Protein SID-1 , 2002, Science.

[63]  N M Dean,et al.  Functional genomics and target validation approaches using antisense oligonucleotide technology. , 2001, Current opinion in biotechnology.

[64]  A. Pasquinelli,et al.  Genes and Mechanisms Related to RNA Interference Regulate Expression of the Small Temporal RNAs that Control C. elegans Developmental Timing , 2001, Cell.

[65]  T. Tuschl,et al.  RNA interference is mediated by 21- and 22-nucleotide RNAs. , 2001, Genes & development.

[66]  R. Carthew,et al.  Heritable gene silencing in Drosophila using double-stranded RNA , 2000, Nature Biotechnology.

[67]  T. Giordano,et al.  RNA as a drug target: methods for biophysical characterization and screening. , 2000, Trends in biotechnology.

[68]  M. Esteban,et al.  Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): Mechanism of action , 2000, Apoptosis.

[69]  P. Sharp,et al.  RNAi Double-Stranded RNA Directs the ATP-Dependent Cleavage of mRNA at 21 to 23 Nucleotide Intervals , 2000, Cell.

[70]  M. Kirby,et al.  Double-stranded RNA injection produces null phenotypes in zebrafish. , 2000, Developmental biology.

[71]  V. Ambros,et al.  The lin-4 regulatory RNA controls developmental timing in Caenorhabditis elegans by blocking LIN-14 protein synthesis after the initiation of translation. , 1999, Developmental biology.

[72]  J. Wolff,et al.  High levels of foreign gene expression in hepatocytes after tail vein injections of naked plasmid DNA. , 1999, Human gene therapy.

[73]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[74]  A. Fire,et al.  Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans , 1998, Nature.

[75]  G. Ruvkun,et al.  Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C. elegans , 1993, Cell.

[76]  Will French.  Function I , 1937 .

[77]  H. Mizuguchi,et al.  Gene therapy for human small-cell lung carcinoma by inactivation of Skp-2 with virally mediated RNA interference , 2005, Gene Therapy.

[78]  Raymond M. Schiffelers,et al.  Pharmaceutical Prospects for RNA Interference , 2004, Pharmaceutical Research.

[79]  M. Stevenson,et al.  Modulation of HIV-1 replication by RNA interference , 2002, Nature.

[80]  P. Glazer,et al.  Gene targeting via triple-helix formation. , 2001, Progress in nucleic acid research and molecular biology.

[81]  P. Reich,et al.  [Letters to nature] , 1975, Nature.

[82]  M. A. Rector,et al.  References and Notes Materials and Methods Som Text Fig. S1 Table S1 References a Microrna in a Multiple- Turnover Rnai Enzyme Complex , 2022 .

[83]  H. Paulson,et al.  For Personal Use. Only Reproduce with Permission the Lancet Publishing Group. Molecular Medicine for the Brain: Silencing of Disease Genes with Rna Interference , 2022 .