Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma.

Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Research Abstract Details 

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Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Abstract Text:

Wenfang Shi,Akseli Hemminki,Jeffrey S Bartlett,

OBJECTIVES: Capsid-modified AAV vectors can mediate enhanced gene transfer to neoplasms characterized by low AAV receptor expression. Here we sought to determine the therapeutic potential of a capsid-modified AAV vector for gene therapy of ovarian carcinoma (OvCa). METHODS: We tested a panel of OvCa cell lines for AAV2-mediated gene transduction and for sensitivity to ganciclovir (GCV) following AAVHSVtk administration. Levels of AAV internalization and attachment receptor were assessed by flow cytometry and immunohistochemistry. The role of receptors in AAV-mediated gene transfer was assessed by competition assays. Finally, we examined the ability of a modified vector with an integrin-binding RGD motif inserted into the AAV capsid to improve gene delivery to OvCa and enhance AAVHSVtk/GCV-mediated killing by cytotoxicity assay. RESULTS: All OvCa cell lines were poorly transduced with AAV2 vectors and showed variably sensitive to AAVHSVtk/GCV. While OvCa cell lines expressed AAV2 internalization receptors (alphav integrins), expression of the AAV2 attachment receptor, HSPG, was variable and not detected on many lines. Analysis of archived clinical specimens showed no detectable HSPG expression on approximately 45% of primary human tumors. Gene transfer to OvCa was increased several fold using the RGD-modified vector. Gene transfer was independent of HSPG and specific to the targeted receptor. Importantly, the RGD-modified capsid markedly increased the ability of the AAVHSVtk to kill OvCa cells in the presence of GCV. CONCLUSIONS: The development of AAV vectors targeted to cell surface receptors other than HSPG will be critical to the advancement of AAV-mediated gene therapy for treating OvCa.

Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Publishing Authors By Initials

W Shi,A Hemminki,JS Bartlett,

For similar genetic structures: plasmids research abstracts see: genetic structures: plasmids research

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Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Gynecologic oncology

VOLUME: 103

Page Numbers: 1054-62

Journal Abbreviation: Gynecol. Oncol.

ISSN: 0090-8258

DAY: 25

MONTH: 07

YEAR: 2006

Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 365304

Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Keywords Mesh Terms:

KEYWORDS: Plasmids

MESH TERMS: metabolism

Chemical & Substance for Abstract: Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma. Information

Substance Name: Heparan Sulfate Proteoglycans

Registry Number: 0

Grant and Affiliation Information for Capsid modifications overcome low heterogeneous expression of heparan sulfate proteoglycan that limits AAV2-mediated gene transfer and therapeutic efficacy in human ovarian carcinoma.

AFFILIATION: Division of Molecular Medicine, Department of Pediatrics, College of Medicine and Public Health, The Ohio State University, Columbus, OH 43210-1393, USA, and Department of Oncology, Helsinki University Central Hospital, Finland.

Country: United States

AGENCY: United States NIAID

GRANT: R21 AI51388

ACRONYM: AI

MEDLINETA: Gynecol Oncol

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