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

Ren-Yuan Bai, Dominic Esposito, Ada J Tam, Frank McCormick, Gregory J Riggins, D Wade Clapp, Verena Staedtke

Gene therapy 2019 Jun

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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.

Citation

Ren-Yuan Bai, Dominic Esposito, Ada J Tam, Frank McCormick, Gregory J Riggins, D Wade Clapp, Verena Staedtke. Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene therapy. 2019 Jun;26(6):277-286