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RNA interference efficiently targets human leukemia driven by a fusion oncogene in vivo

Leukemia volume 32, pages 224–226 (2018)Cite this article

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Despite the wide therapeutic potential of RNA interference (RNAi), clinical progress has been slow with only a few examples of successful translation. Efficient knockdown of hepatic transthyretin (87%) in patients with transthyretin amyloidosis lasted for several weeks after a single dose.1 Furthermore, in a phase I clinical trial, a single dose of inclisiran (small interfering RNA (siRNA) against the PCSK9 mRNA) efficiently suppressed serum cholesterol for 6 months.2 However, these studies suggested that siRNA delivery beyond the liver is not yet feasible in the clinic and thus limits the potential benefit of RNAi. Lipid nanoparticles (LNPs) containing ionizable cationic lipids embody the most advanced delivery platform for systemic administration of RNAi therapeutics.3 Our study provides a preclinical proof-of-concept that RNAi therapeutics can be exploited against leukemia cells using LNPs as a delivery tool, in a patient-derived B-cell acute lymphoblastic leukemia (ALL) xenograft mouse model.

Chromosomal translocations are considered driver mutations in leukemogenesis that are usually present in all leukemic cells and are retained during relapse.4 Seventy five percent of pediatric ALL patients harbor gross chromosomal aberrations, with ETV6-RUNX1, TCF3-PBX1, MLL rearrangements and BCR-ABL1 being the most relevant translocations.5 Continuous efforts have been made to target fusion oncogenes by delivering siRNAs in vitro such as anti-BCR-ABL siRNA in K562 cells6 and anti-MLL-AF9 siRNA in THP1 cells,7 and in vivo such as anti-SS18-SSX1 siRNA in a synovial sarcoma xenograft model8 and anti-TMPRSS2-ERG siRNA in a prostate cancer xenograft model.9 Anti-BCR-ABL siRNA was also administered intravenously (i.v.) in an imatinib resistant chronic myeloid leukemia (CML) patient and showed efficient knockdown of the BCR-ABL fusion gene with good tolerability.10

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Acknowledgements

We thank Silke Glowotz, Martin Wichmann, Anitha Thomas and Colin Walsh for technical support. We express sincere thanks to the patients for their participation in the study. We thank Prof. Dr Alf Lamprecht and Dr Manusmriti Singh for providing us nanoparticles during the initial experiments. We thank the staff of the Central Animal Facility and Matthias Ballmaier from the Cell Sorting Core Facility (supported in part by the Braukmann-Wittenberg-Herz-Stiftung and the Deutsche Forschungsgemeinschaft) of Hannover Medical School. This study was supported by the Rudolf-Bartling Stiftung, an ERC grant under the European Union’s Horizon 2020 research and innovation programme (No. 638035), by grants 110284, 110287, 110292 and 111267 from Deutsche Krebshilfe; grant DJCLS R13/14 from the Deutsche José Carreras Leukämie-Stiftung e.V; the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx); DFG grant HE 5240/5-1, HE 5240/5-2 and HE 5240/6-1; grants from Dieter-Schlag Stiftung and a Terry Fox Foundation Program Project Award to RKH.

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Authors and Affiliations

  1. Department of Hematology, Hemostasis, Oncology and Stem cell Transplantation, Hannover Medical School, Hannover, Germany

    N Jyotsana, A Sharma, A Chaturvedi, M Scherr, M Eder, F Thol, A Ganser & M Heuser

  2. Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany

    F Kuchenbauer

  3. Nanotechnology Department, Laser Zentrum Hannover, Hannover, Germany

    L Sajti & A Barchanski

  4. Department of Cell Biology, Center of Anatomy, Hannover Medical School, Hannover, Germany

    R Lindner

  5. Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

    F Noyan

  6. Clinic for Neurology, Hannover Medical School, Hannover, Germany

    K-W Sühs

  7. Department of Clinical Chemistry, Hannover Medical School, Hannover, Germany

    D Grote-Koska & K Brand

  8. Axolabs GmBH, Kulmbach, Germany

    H-P Vornlocher

  9. Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    M Stanulla

  10. Department of Oncology and Children’s Research Centre, University Children’s Hospital Zürich, Zürich, Switzerland

    B Bornhauser & J-P Bourquin

  11. Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada

    R K Humphries

  12. Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada

    R K Humphries

  13. Precision NanoSystems, Inc., Vancouver, British Columbia, Canada

    E Ramsay

  14. Department of Biochemistry and Molecular Biology, University of British Columbia, Health Sciences Mall, Vancouver, British Columbia, Canada

    P Cullis

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  1. N Jyotsana
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Corresponding author

Correspondence to M Heuser.

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Competing interests

Euan Ramsay is an employee of Precision Nanosystems. Pieter Cullis is founder of Precision Nanosystems. The other authors have no conflicts of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Jyotsana, N., Sharma, A., Chaturvedi, A. et al. RNA interference efficiently targets human leukemia driven by a fusion oncogene in vivo. Leukemia 32, 224–226 (2018). https://doi.org/10.1038/leu.2017.269

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