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siRNA and miRNA Gene Silencing pp 1–16Cite as

Therapeutic Targeting of Gene Expression by siRNAs Directed Against BCR-ABL Transcripts in a Patient with Imatinib-Resistant Chronic Myeloid Leukemia

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 487))

Abstract

Within the recent years, RNA interference (RNAi) has become an almost-standard method for in vitro knockdown of any target gene of interest. Now, one major focus is to further explore its potential in vivo, including the development of novel therapeutic strategies. From the mechanism, it becomes clear that small interfering RNAs (siRNAs) play a pivotal role in triggering RNAi. Thus, the efficient delivery of target gene-specific siRNAs is one major challenge in the establishment of therapeutic RNAi. Here we show that in vivo application of targeted nonvirally delivered synthetic bcr-abl siRNA in a female patient with recurrent Philadelphia chromosome positive chronic myeloid leukemia (CML) resistant to imatinib (Y253F mutation) and chemotherapy after allogeneic hematopoietic stem cell transplantation can silence the expression bcr-abl gene. We found a remarkable inhibition of the overexpressed bcr-abl oncogene resulting in increased apoptosis of CML cells. In vivo siRNA application was well tolerated without any clinically adverse events. Our findings imply that the clinical application of synthetic siRNA is feasible, safe and has real potential for genetic-based therapies using synthetic nonviral carriers.

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Acknowledgments

The authors would like to thank Katja Ahrens, Melanie Kroll, Silke Gottwald, Ines Riepenhoff, and Christiane Schary for their excellent technical execution of the PCR analyses.

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Authors and Affiliations

  1. M. Koldehoff (馓)Department of Bone Marrow Transplantation, University of Duisburg-Essen, Hufelandstr. 55, 45122, Essen, Germany

    Michael Koldehoff & Ahmet H. Elmaagacli

Authors
  1. Michael Koldehoff
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  2. Ahmet H. Elmaagacli
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Corresponding author

Correspondence to Michael Koldehoff .

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Editors and Affiliations

  1. Institute for Cancer Research, Dept. Immunology, Norwegian Radium Hospital, Montebello, Oslo, 0310, Norway

    Mouldy Sioud

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© 2009 Humana Press, a part of Springer Science+Business Media, LLC

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Koldehoff, M., Elmaagacli, A. (2009). Therapeutic Targeting of Gene Expression by siRNAs Directed Against BCR-ABL Transcripts in a Patient with Imatinib-Resistant Chronic Myeloid Leukemia. In: Sioud, M. (eds) siRNA and miRNA Gene Silencing. Methods in Molecular Biology, vol 487. Humana Press. https://doi.org/10.1007/978-1-60327-547-7_22

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  • DOI: https://doi.org/10.1007/978-1-60327-547-7_22

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  • Publisher Name: Humana Press

  • Print ISBN: 978-1-60327-546-0

  • Online ISBN: 978-1-60327-547-7

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