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Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors

Gene Therapy volume 26, pages 277–286 (2019)Cite this article

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Abstract

Neurofibromatosis type 1, including the highly aggressive malignant peripheral nerve sheath tumors (MPNSTs), is featured by the loss of functional neurofibromin 1 (NF1) protein resulting from genetic alterations. A major function of NF1 is suppressing Ras activities, which is conveyed by an intrinsic GTPase-activating protein-related domain (GRD). In this study, we explored the feasibility of restoring Ras GTPase via exogenous expression of various GRD constructs, via gene delivery using a panel of adeno-associated virus (AAV) vectors in MPNST and human Schwann cells (HSCs). We demonstrated that several AAV serotypes achieved favorable transduction efficacies in those cells and a membrane-targeting GRD fused with an H-Ras C-terminal motif (C10) dramatically inhibited the Ras pathway and MPNST cells in a NF1-specific manner. Our results opened up a venue of gene replacement therapy in NF1-related tumors.

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Acknowledgements

We thank Mr. Richard (Lee) Blosser of BKI flow center for his valuable help in flow cytometry. This work was supported by Francis S. Collins Scholar Program (V.S.), 1K08CA230179–01 (V.S.), DHART-SPORE IN4689861JHU (V.S.), Children’s Tumor Foundation 2016A-05–008 (V.S.), 1R03CA178118–01A1 (R.Y.B.), and DOD W81XWH1810236 (R.Y.B.).

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Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ren-Yuan Bai & Gregory J. Riggins

  2. NCI RAS Initiative, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, MD, 21701, USA

    Dominic Esposito & Frank McCormick

  3. Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Ada J. Tam

  4. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    D. Wade Clapp

  5. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Verena Staedtke

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  1. Ren-Yuan Bai
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Correspondence to Ren-Yuan Bai or Verena Staedtke.

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Conflict of interest

A provisional patent application on Rasopathy treatment listing R.Y.B. and V.S. as co-inventors was filed by JHU. D.E., A.J.T., G.J.R., D.W.C. and F.M. have no conflicts of interest to declare.  

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Bai, RY., Esposito, D., Tam, A.J. et al. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene Ther 26, 277–286 (2019). https://doi.org/10.1038/s41434-019-0080-9

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