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

被引：26

作者：

Bai, Ren-Yuan ^{[1
]}

Esposito, Dominic ^{[2
]}

Tam, Ada J. ^{[3
]}

McCormick, Frank ^{[2
]}

Riggins, Gregory J. ^{[1
]}

Clapp, D. Wade ^{[4
]}

Staedtke, Verena ^{[5
]}

机构：

[1] Johns Hopkins Univ, Sch Med, Dept Neurosurg, Baltimore, MD 21205 USA

[2] Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, NCI RAS Initiat, Frederick, MD 21701 USA

[3] Johns Hopkins Univ, Sch Med, Bloomberg Kimmel Inst Canc Immunotherapy, Baltimore, MD USA

[4] Indiana Univ Sch Med, Dept Pediat, Indianapolis, IN 46202 USA

[5] Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA

来源：

GENE THERAPY | 2019年 / 26卷 / 06期

关键词：

NERVE SHEATH TUMORS; GAP-RELATED DOMAIN; PERIPHERAL-NERVE; IN-VITRO; ADENOASSOCIATED VIRUSES; LEGIUS SYNDROME; RAS; NEUROFIBROMIN; VECTORS; TRANSDUCTION;

D O I：

10.1038/s41434-019-0080-9

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：277 / 286

页数：10

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