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

doi:10.1038/s41434-019-0080-9

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

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.

Original language	English (US)
Pages (from-to)	277-286
Number of pages	10
Journal	Gene Therapy
Volume	26
Issue number	6
DOIs	https://doi.org/10.1038/s41434-019-0080-9
State	Published - Jun 1 2019

ASJC Scopus subject areas

Molecular Medicine
Molecular Biology
Genetics

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title = "Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors",

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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AU - Bai, Ren Yuan

AU - Esposito, Dominic

AU - Tam, Ada J.

AU - McCormick, Frank

AU - Riggins, Gregory J.

AU - Wade Clapp, D.

AU - Staedtke, Verena

PY - 2019/6/1

Y1 - 2019/6/1

N2 - 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.

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

Abstract

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