Open AccessLipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo
Author(s) -
Nidhi Jyotsana,
Amit Sharma,
Anuhar Chaturvedi,
Ramachandramouli Budida,
Michaela Scherr,
Florian Kuchenbauer,
Robert Lindner,
Fatih Noyan,
KurtWolfram Sühs,
Martin Stangel,
Denis Grote-Koska,
Korbinian Brand,
HansPeter Vornlocher,
Matthias Eder,
Felicitas Thol,
Arnold Ganser,
R. Keith Humphries,
Euan Ramsay,
Pieter R. Cullis,
Michael Heuser
Publication year - 2019
Publication title -
annals of hematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.079
H-Index - 80
eISSN - 1432-0584
pISSN - 0939-5555
DOI - 10.1007/s00277-019-03713-y
Subject(s) - in vivo , myeloid leukemia , oncogene , leukemia , cancer research , small interfering rna , rna interference , cationic liposome , haematopoiesis , chemistry , abl , medicine , biology , transfection , immunology , stem cell , rna , apoptosis , microbiology and biotechnology , signal transduction , biochemistry , tyrosine kinase , gene , cell cycle
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.