Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2019-05-18

AUTHORS

Nidhi Jyotsana, Amit Sharma, Anuhar Chaturvedi, Ramachandramouli Budida, Michaela Scherr, Florian Kuchenbauer, Robert Lindner, Fatih Noyan, Kurt-Wolfram Sühs, Martin Stangel, Denis Grote-Koska, Korbinian Brand, Hans-Peter Vornlocher, Matthias Eder, Felicitas Thol, Arnold Ganser, R. Keith Humphries, Euan Ramsay, Pieter Cullis, Michael Heuser

ABSTRACT

Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients. More... »

PAGES

1905-1918

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  • Journal

    TITLE

    Annals of Hematology

    ISSUE

    8

    VOLUME

    98

    Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s00277-019-03713-y

    DOI

    http://dx.doi.org/10.1007/s00277-019-03713-y

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1114740199

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/31104089


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