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Cited by 38Virus-based gene therapy researchNeurofibromatosis and Schwannoma CasesRNA Interference and Gene Delivery

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

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Bai, Ren-Yuan, Esposito, Dominic, Tam, Ada J., McCormick, Frank, Riggins, Gregory J., Wade Clapp, D., Staedtke, Verena·2019·Gene Therapy
DOI 10.1038/s41434-019-0080-9PMC PMC6588423
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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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  • Several AAV serotypes could inhibit proliferation (i.e. the Ras pathway) in test cells.

    “This led them to demonstrate that several AAV serotypes could inhibit proliferation (i.e. the Ras pathway) in test cells.”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [112]

    In the Results section (page unavailable), several AAV serotypes were compared for delivery of an EGFP marker, not for inhibition of proliferation. The paper reports reduced Ras-pathway signaling and growth in MPNST cells using NF1-GRD delivered by AAV-DJ; it does not demonstrate that several serotypes inhibit proliferation. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Bai and colleagues used a panel of AAV vectors to express various GRD constructs in malignant peripheral nerve sheath tumors as well as in human Schwann cells.

    “Bai and colleagues used a panel of AAV vectors to express various GRD constructs in malignant peripheral nerve sheath tumors as well as in human Schwann cells [112].”

    From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [112]

    The Results report testing a panel of AAV vectors in MPNST and primary human Schwann cells, but that panel expressed EGFP to measure transduction. The GRD and GRD-C10 constructs were tested using AAV-DJ, not the panel of vectors; the Results also discuss their effects in Schwann cells. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Bai, R.-Y., Esposito, D., Tam, A. J., McCormick, F., Riggins, G. J., Wade Clapp, D., & Staedtke, V.
Affiliations
  • Johns Hopkins University (US)
  • Frederick National Laboratory for Cancer Research (US)
Corresponding author
  • Bai, Ren-Yuan
  • Staedtke, Verena
ORCID
Venue
Gene Therapy
Publisher
Springer Science and Business Media LLC
Published
2019-05-24
Volume
26
Issue
6
Pages
277-286
ISSN
  • 0969-7128 (ISSN-L)
  • 1476-5462
DOI
10.1038/s41434-019-0080-9
PMC
PMC6588423
OpenAlex
W2945528810
Cited by
38
References
2
Citations by year
2026: 3 · 2025: 8 · 2024: 6 · 2023: 1 · 2022: 9 · 2021: 5 · 2020: 5 · 2019: 1
FWCI
3.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Gene Therapy (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
  • PMC
Funders
  • U.S. Department of Health & Human Services | NIH | National Cancer Institute (1R03CA178118-01A1, 1K08CA230179-01)
  • United States Department of Defense | United States Army | U.S. Army Research, Development and Engineering Command | Army Research Office (W81XWH1810236)
  • Children's Tumor Foundation (2016A-05-008)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
neurofibromatosis type 1, malignant peripheral nerve sheath tumor, neurofibromin 1, adeno-associated virus vectors, gene replacement therapy, Schwann cells, AAV serotypes, transduction efficiency
MeSH terms
Protein Domains, Dependovirus, Cell Line, Cells, Cultured, Feasibility Studies, Genetic Vectors, Humans, Neurofibromatosis 1, Schwann Cells, Genetic Therapy, ras Proteins, Neurofibromin 1, Cell Line, Tumor

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