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Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and causes efficient target de-repression: a proof of concept

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Abstract

Over-expressed microRNAs (miRs) are promising new targets in glioblastoma (GBM) therapy. Inhibition of over-expressed miRs has been shown to diminish GBM proliferation, invasion and angiogenesis, indicating a significant therapeutic potential. However, the methods utilized for miR inhibition have had low translational potential. In clinical trials convection-enhanced delivery (CED) has been applied for local delivery of compounds in the brain. The aim of this study was to determine if safe and efficient miR inhibition was possible by CED of an anti-miR. We used a highly invasive GBM orthotopic xenograft model and targeted a well-validated miR, let-7a, with a 2′-O-methoxyethyl anti-miR with a combined phosphodiester/phosphorothioate backbone to establish an initial proof of concept. In vitro, anti-let-7a was delivered unassisted to the patient-derived T87 glioblastoma spheroid culture. In vivo, anti-let-7a or saline were administered by CED into orthotopic T87-derived tumors. After 1 month of infusion, tumors were removed and tumor mRNA levels of the target-gene High-mobility group AT-hook 2 (HMGA2) were determined. In vitro, 5 days inhibition was superior to 1 day at de-repressing the let-7a target HMGA2 and the inhibition was stable for 24 h. In vivo, anti-miR integrity was preserved in the pumps and no animals showed signs of severe adverse effects attributable to the anti-miR treatment. HMGA2 tumor level was significantly de-repressed in the anti-miR treated animals. The results showed—as an initial proof of concept—that miRs can be efficiently inhibited using CED delivery of anti-miR. The next step is to apply CED for anti-miR delivery focusing on key oncogenic miRs.

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Acknowledgments

This work was supported by grants from Odense University Hospital, Region of Southern Denmark, Familien Erichsens Foundation, P A Messerschmidt & Hustrus foundation. The technical assistance from Helle Wohlleben and Tanja D. Højgaard, Department of Pathology, Odense University Hospital and Thomas M. Vincent and Kai Liu, Regulus Therapeutics, Inc. is appreciated.

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Authors and Affiliations

  1. Department of Neurosurgery, Odense University Hospital, Sdr. Boulevard 29, 5000, Odense C, Denmark

    Bo Halle, Mette K. Schulz & Claus Andersen

  2. Department of Pathology, Odense University Hospital, Winsløwparken 15, 5000, Odense C, Denmark

    Bo Halle, Charlotte Aaberg-Jessen, Stine S. Jensen & Bjarne W. Kristensen

  3. Institute of Clinical Research, University of Southern Denmark, Winsløwparken 19.3, 5000, Odense C, Denmark

    Bo Halle, Charlotte Aaberg-Jessen, Stine S. Jensen, Mette K. Schulz, Claus Andersen & Bjarne W. Kristensen

  4. Regulus Therapeutics, Inc. 3545 John Hopkins Ct., Suite 210, San Diego, CA, 92121-1121, USA

    Eric G. Marcusson

  5. Department of Neurobiology Research, Institute of Molecular Medicine, University of Southern Denmark, Winsløwparken 21, 5000, Odense C, Denmark

    Morten Meyer

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  1. Bo Halle
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Correspondence to Bo Halle.

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Eric Marcusson was Senior Director of Oncology at Regulus Therapeutics. No other authors declared any conflict of interest.

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The experiments in this study complied with the laws of the countries in which they were performed.

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Halle, B., Marcusson, E.G., Aaberg-Jessen, C. et al. Convection-enhanced delivery of an anti-miR is well-tolerated, preserves anti-miR stability and causes efficient target de-repression: a proof of concept. J Neurooncol 126, 47–55 (2016). https://doi.org/10.1007/s11060-015-1947-2

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