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. Clapp, Verena Staedtke

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)277-286
Number of pages10
JournalGene Therapy
Volume26
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Neurofibromin 1
GTPase-Activating Proteins
Dependovirus
Genetic Therapy
Neurilemmoma
Neoplasms
ras Proteins
Neurofibromatosis 1
Schwann Cells
Cell Membrane
Protein Domains
Genes
Proteins

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Bai, R. Y., Esposito, D., Tam, A. J., McCormick, F., Riggins, G. J., Clapp, D., & Staedtke, V. (2019). Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. Gene Therapy, 26(6), 277-286. https://doi.org/10.1038/s41434-019-0080-9

Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. / Bai, Ren Yuan; Esposito, Dominic; Tam, Ada J.; McCormick, Frank; Riggins, Gregory J.; Clapp, D.; Staedtke, Verena.

In: Gene Therapy, Vol. 26, No. 6, 01.06.2019, p. 277-286.

Research output: Contribution to journalArticle

Bai, RY, Esposito, D, Tam, AJ, McCormick, F, Riggins, GJ, Clapp, D & Staedtke, V 2019, 'Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors', Gene Therapy, vol. 26, no. 6, pp. 277-286. https://doi.org/10.1038/s41434-019-0080-9
Bai, Ren Yuan ; Esposito, Dominic ; Tam, Ada J. ; McCormick, Frank ; Riggins, Gregory J. ; Clapp, D. ; Staedtke, Verena. / Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors. In: Gene Therapy. 2019 ; Vol. 26, No. 6. pp. 277-286.
@article{d0ad1670595e4bdba40b42a59b69037f,
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.",
author = "Bai, {Ren Yuan} and Dominic Esposito and Tam, {Ada J.} and Frank McCormick and Riggins, {Gregory J.} and D. Clapp and Verena Staedtke",
year = "2019",
month = "6",
day = "1",
doi = "10.1038/s41434-019-0080-9",
language = "English (US)",
volume = "26",
pages = "277--286",
journal = "Gene Therapy",
issn = "0969-7128",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Feasibility of using NF1-GRD and AAV for gene replacement therapy in NF1-associated tumors

AU - Bai, Ren Yuan

AU - Esposito, Dominic

AU - Tam, Ada J.

AU - McCormick, Frank

AU - Riggins, Gregory J.

AU - 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.

UR - http://www.scopus.com/inward/record.url?scp=85066915205&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85066915205&partnerID=8YFLogxK

U2 - 10.1038/s41434-019-0080-9

DO - 10.1038/s41434-019-0080-9

M3 - Article

VL - 26

SP - 277

EP - 286

JO - Gene Therapy

JF - Gene Therapy

SN - 0969-7128

IS - 6

ER -