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Autor     Mario Stevenson
Titel    Therapeutic Potential of RNA Interference
Zeitschrift    The New England Journal of Medicine
Ausgabe    351
Datum    October 2004
Seiten    1772-1777
DOI    10.1056/NEJMra045004
URL    http://www.nejm.org/doi/full/10.1056/NEJMra045004

Literaturverz.   

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Fußnoten    nein
Fragmente    4


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1.2.2 Therapeutic applications of RNAi

The therapeutic applications of RNAi are potentially enormous. The genetic etiology of many disorders has now been defined and, in some cases, has been targeted by RNAi in in vitro and in vivo model systems. Because the specificity of RNAi is governed by sequence complementarity between the siRNA and the target RNA, the most obvious application would be to treat diseases in which genetic polymorphisms within the disease-inducing gene in a particular lesion or tumor can be targeted for degradation without affecting RNA from wild-type alleles.

Therapeutic Applications

The therapeutic applications of RNAi are potentially enormous. The genetic etiology of many disorders has now been defined and, in some cases, has been targeted by RNAi in in vitro and in vivo model systems. Because the specificity of RNAi is governed by sequence complementarity between the siRNA and the target RNA, the most obvious application would be to treat diseases in which genetic polymorphisms within the disease-inducing gene in a particular lesion or tumor can be targeted for degradation without affecting RNA from wild-type alleles.

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[2.] Ww/Fragment 013 12 - Diskussion
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The translocation of the Philadelphia chromosome (Ph) generates a fusion gene called BCR-ABL. The translation product of this gene creates a constitutively active protein tyrosine kinase that induces and maintains leukemic transformation in chronic myelogenous leukemia and Ph-positive acute lymphoblastic leukemia. The siRNAs specific for the BCR-ABL transcript have been shown to silence the oncogenic fusion transcripts without affecting expression levels of normal c-ABL and c-BCR transcripts (Scherr et al, 2003; Wohlbold et al, 2003).

Pancreatic and colon carcinomas, in which RAS genes are often mutated, provide another example for potential RNAi applications. In many cases, the RAS oncogenes contain point mutations that differ by a single-base mutation from their normal counterparts. The use of retroviral vectors to introduce interfering RNAs specific for an oncogenic variant of KRAS (called K-RASV12) reduced the level of K-RASV12 transcripts and resulted in a loss of anchorage-independent growth and tumorigenicity (Brummelkamp et al, 2002). Studies of this kind provided proof-of-concept data for RNAi-based strategies aiming to reverse tumorigenesis.

1.2.2.2 Infectious diseases

The translocation of the Philadelphia chromosome (Ph) generates a fusion gene called BCR-ABL. The translation product of this gene creates a constitutively active protein tyrosine kinase that induces and maintains leukemic transformation in chronic myelogenous leukemia and Ph-positive acute lymphoblastic leukemia. The siRNAs specific for the BCR-ABL transcript have been shown to silence the oncogenic fusion transcripts without affecting expression levels of normal c-ABL and c-BCR transcripts.20,21

Pancreatic and colon carcinomas, in which RAS

[Seite 1775]

genes are often mutated, provide another example. In many cases, the RAS oncogenes contain point mutations that differ by a single-base mutation from their normal counterparts. The use of retroviral vectors to introduce interfering RNAs specific for an oncogenic variant of K-RAS (called K-RASV12) reduces the level of K-RASV12 transcripts and effects a loss of anchorage-independent growth and tumorigenicity.22,23 Studies of this kind provide proof-of-concept for RNAi-based strategies aimed at reversing tumorigenesis. [...]

[...]

Infectious Diseases


20. Scherr M, Battmer K, Winkler T, Heidenreich O, Ganser A, Eder M. Specific inhibition of bcr-abl gene expression by small interfering RNA. Blood 2003;101: 1566-9.

21. Wohlbold L, van der Kuip H, Miething C, et al. Inhibition of bcr-abl gene expression by small interfering RNA sensitizes for imatinib mesylate (STI571). Blood 2003; 102:2236-9.

22. Brummelkamp TR, Bernards R, Agami R. Stable suppression of tumorigenicity by virus-mediated RNA interference. Cancer Cell 2002;2:243-7.

23. Wilda M, Fuchs U, Wossmann W, Borkhardt A. Killing of leukemic cells with a BCR/ABL fusion gene by RNA interference (RNAi). Oncogene 2002;21:5716-24.

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[3.] Ww/Fragment 015 11 - Diskussion
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Delivery is probably the single biggest obstacle to the development of RNAi-based therapeutic agents. Trigger RNAs (dsRNAs from which siRNAs are derived by the action of Dicer) can be expressed from vectors or delivered as artificial siRNAs. A variety of strategies to express interfering RNAs with the use of plasmid and virus vector-based cassettes have been explored (Li et al, 2002; Dykxhoorn et al, 2003). Well-documented hazards of inserting foreign vector sequences into chromosomal DNA include insertional activation and inactivation of cellular genes. Direct (intravenous) administration of siRNAs would require siRNAs that are modified to be resistant to nucleases and perhaps conjugated with a ligand to target the siRNA to specific tissues. In mice, intravenous introduction of Fas siRNAs leads to specific silencing of Fas mRNA in the liver (Song et al, 2003), so in principle, unmodified siRNAs can be taken up by the liver and perhaps other tissues. It is not clear, however, whether there are selective tissue sites for the uptake of siRNAs and whether the lymphoid system or the brain, for instance, is accessible by this route. Furthermore, the silencing effect of siRNAs is short-lived, because the siRNAs eventually decay within the cell. In addition to the danger of using vectors that integrate into the genome, the expression or injection of siRNAs may also have unwanted biologic side effects. Researchers are continually finding new cellular processes in which RNAi is involved. Therefore, a stoichiometric excess of a virus-specific siRNA, for [example, could saturate RNAi and interrupt the pathway’s normal functions in the cell. Interferons, which form part of the host’s defense against viral infection, are activated by long dsRNA (more than 500 bp).] Delivery is probably the single biggest obstacle to the development of RNAi-based therapeutic agents. Trigger RNAs (dsRNAs from which siRNAs are derived by the action of Dicer) can be expressed from vectors or delivered as artificial siRNAs. A variety of strategies to express interfering RNAs with the use of plasmid and virus vector-based cassettes have been explored.7,37 Well-documented hazards of inserting foreign vector sequences into chromosomal DNA include insertional activation and inactivation of cellular genes.

Direct (e.g., intravenous) administration of siRNAs would require siRNAs that are modified to be resistant to nucleases and perhaps conjugated with a ligand to target the siRNA to specific tissues. In mice, intravenous introduction of Fas siRNAs leads to specific silencing of Fas mRNA in the liver,25 so in principle, unmodified siRNAs can be taken up by the liver and perhaps other tissues. It is not clear, however, whether there are selective tissue sites for the uptake of siRNAs and whether the lymphoid system or the brain, for instance, is accessible by this route. Furthermore, the silencing effect of siRNAs is short-lived, because the siRNAs eventually decay within the cell.

In addition to the danger of using vectors that integrate into the genome, the expression or injection of siRNAs may also have untoward biologic effects. Researchers are continually finding new cellular processes in which RNAi is involved. Therefore, a stoichiometric excess of a virus-specific siRNA, for example, could saturate RNAi and interrupt the pathway's normal functions in the cell.

Interferons, which form part of the host's defense against viral infection, are activated by long dsRNA (more than 500 bp).


7. Dykxhoorn DM, Novina CD, Sharp PA. Killing the messenger: short RNAs that silence gene expression. Nat Rev Mol Cell Biol 2003;4:457-67.

25. Song E, Lee SK, Wang J, et al. RNA interference targeting Fas protects mice from fulminant hepatitis. Nat Med 2003;9:347- 51.

37. Li H, Li WX, Ding SW. Induction and suppression of RNA silencing by an animal virus. Science 2002;296:1319-21.

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[Therefore, a stoichiometric excess of a virus-specific siRNA, for] example, could saturate RNAi and interrupt the pathway’s normal functions in the cell. Interferons, which form part of the host’s defense against viral infection, are activated by long dsRNA (more than 500 bp). It is now apparent that siRNAs (Sledz et al, 2003) as well as shRNAs expressed from DNA vectors (Bridge et al, 2003) can trigger the activation of interferons. However, there is no evidence that the activation of interferons by short RNAs influences the degree or specificity of RNA silencing. In addition, these effects have to be reconciled with the manufacturing in cells of many thousands of copies of pre-miRNAs (Lagos et al, 2001) that do not appear to activate interferons. Therefore, a stoichiometric excess of a virus-specific siRNA, for example, could saturate RNAi and interrupt the pathway's normal functions in the cell.

Interferons, which form part of the host's defense against viral infection, are activated by long dsRNA (more than 500 bp). It is now apparent that siRNAs45 as well as short hairpin RNAs (short sequences of RNA that make tight hairpin turns and can be used to silence gene expression) expressed from DNA vectors46 can trigger the activation of interferons. However, there is no evidence that the activation of interferons by short RNAs influences the degree or specificity of RNA silencing. In addition, these effects have to be reconciled with the manufacturing in cells of many thousands of copies of pre-micro RNAs47,48,49 that do not appear to activate interferons.


45. Sledz CA, Holko M, de Veer MJ, Silverman RH, Williams BR. Activation of the interferon system by short-interfering RNAs. Nat Cell Biol 2003;5:834-9.

46. Bridge AJ, Pebernard S, Ducraux A, Nicoulaz AL, Iggo R. Induction of an interferon response by RNAi vectors in mammalian cells. Nat Genet 2003;34:263-4.

47. Lau NC, Lim LP, Weinstein EG, Bartel DP. An abundant class of tiny RNAs with probable regulatory roles in Caenorhabditis elegans. Science 2001;294:858-62.

48. Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science 2001;294:862-4.

49. Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science 2001;294:853-8.

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