Genetic Targeting Strategies for Adenovirus

Noureddini, Sam C.; Curiel, David T.

doi:10.1021/mp050045c

Cited by 65 publications

(49 citation statements)

References 62 publications

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“…The Ad5 capsid is mainly composed of penton-base and hexon, with the minor capsid protein pIX exerting a cement function, whereas the trimeric fiber with its fiber shaft and fiber knob domain is protruding from the virion surface. 1 The cellular entry of Ad5 in vitro is well described and occurs via a multiple-step mechanism [1][2][3] : first, the globular fiber knob domain, located at the distal end of the fiber homotrimers extending from the 12 capsid vertices, binds to its native cell-surface receptor, the coxsackie and adenovirus receptor (CAR). Following attachment, the Arg, Gly, Asp (RGD) motif of the capsid penton-base interacts with cell-surface a v integrins.…”

Section: Introductionmentioning

confidence: 99%

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

et al. 2007

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Previously, we have identified a tumor cell-specific peptide, HEW, by panning of phage display libraries on the human colorectal cancer cell line WiDr. In this report we demonstrate that this peptide can modify the infection properties of adenovirus vectors. Increased infectivity of replication-deficient adenovirus 5 vectors in WiDr cells was observed upon genetic insertion of the HEW peptide in the HI loop of the fiber knob. Moreover, whereas the coxsackie and adenovirus receptor (CAR)-ablating fiber mutation S408E abolished apparent infection in CAR-positive WiDr cells, the insertion of HEW completely restored infectivity toward these cells in vitro. To assess whether the de-and re-targeted infection profile was maintained in vivo, the fiber-modified adenovirus vectors were injected intratumorally or intravenously in WiDr tumor-bearing Swiss nu/nu mice. No significant differences in efficiency of infection could be observed suggesting alternative viral uptake mechanisms in vivo. Next, we have included the fiber shaft mutation S* in our studies, which was described to confer a de-targeted phenotype in vivo. Reduced gene transfer due to the S* mutation both in vitro and in vivo could be confirmed. Insertion of HEW in the HI knob loop of shaft-mutated fiber, however, did not rescue infectivity in target cells neither in vitro nor in vivo. We demonstrate the efficient ligand-mediated re-targeting of adenoviral vector infection to the human cancer cell line WiDr. The lack of apparent re-targeting in the in vivo situation is described.

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Section: Introductionmentioning

confidence: 99%

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

et al. 2007

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“…For efficient targeting of Ad5, a first major task is to ablate the virion's natural tropism, and this ablation has been achieved by introducing mutations into the knob, hexon, and/or penton base within motifs mediating interactions with cell-surface molecules or blood components, leading to reduced transduction efficiency (13)(14)(15)(16)(17)(18)(19). The second challenge is to retarget the Ad5 specifically to the diseased cells/tissue.…”

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confidence: 99%

Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters

Dreier

Honegger

Hess

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Adenoviruses (Ads) have shown promise as vectors for gene delivery in clinical trials. Efficient viral targeting to a tissue of choice requires both ablation of the virus' original tropism and engineering of an efficient receptor-mediated uptake by a specific cell population. We have developed a series of adapters binding to the virus with such high affinity that they remain fully bound for >10 d, block its natural receptor binding site and mediate interaction with a surface receptor of choice. The adapter contains two fused modules, both consisting of designed ankyrin repeat proteins (DARPins), one binding to the fiber knob of adenovirus serotype 5 and the other binding to various tumor markers. By solving the crystal structure of the complex of the trimeric knob with three bound DARPins at 1.95-Å resolution, we could use computer modeling to design a link to a trimeric protein of extraordinary kinetic stability, the capsid protein SHP from the lambdoid phage 21. We arrived at a module which binds the knob like a trimeric clamp. When this clamp was fused with DARPins of varying specificities, it enabled adenovirus serotype 5-mediated delivery of a transgene in a human epidermal growth factor receptor 2-, epidermal growth factor receptor-, or epithelial cell adhesion molecule-dependent manner with transduction efficiencies comparable to or even exceeding those of Ad itself. With these adapters, efficiently produced in Escherichia coli, Ad can be converted rapidly to new receptor specificities using any ligand as the receptor-binding moiety. Prefabricated Ads with different payloads thus can be retargeted readily to many cell types of choice.protein design | tumor targeting | viral retargeting | X-ray crystallography | protein engineering

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“…Consequently, genetic manipulations to alter Ad tropism have directed largely at the fiber and penton base, and various modifications have been made to the proteins with appreciable success in specific targeting but without structural or functional perturbation of Ad vectors. 56 Incorporation of ligands such as RGD and polylysine (pK) motifs, for targeting integrins and heparin receptor, respectively, at the fiber knob's C-terminus or HI-loop was shown to improve CAR-independent transduction while expanding Ad tropism, 57,58 with the latter locale permitting inserts of a larger size (up to 100 residues). Replacement of the knob or the whole fiber with various ligand fusions containing a trimerizing domain from other viral or nonviral proteins that could form a trimeric structure similar to the knob was able to both ablate the Ads native CAR tropism and confer a ligand-based alternate tropism, [59][60][61] so was switching the knob or fiber with serotypes of Ads with non-CAR receptors.…”

Section: Modifications To Improve the Targeting Of Ad Vectorsmentioning

confidence: 99%

Recent developments in the use of adenoviruses and immunotoxins in cancer gene therapy

et al. 2007

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Despite setbacks in the past and apparent hurdles ahead, gene therapy is advancing toward reality. The past several years have witnessed this new field of biomedicine developing rapidly both in breadth and depth, especially for the treatment of cancer, thanks largely to the better understanding of molecular and genetic basis of oncogenesis and the development of new and improved vectors and technologies for gene delivery and targeting. This article is intended to provide a brief review of recent advances in cancer gene therapy using adenoviruses, both as vectors and as oncolytic agents, and some of the recent progress in the development of immunotoxins for use in cancer gene therapy.

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Genetic Targeting Strategies for Adenovirus

Cited by 65 publications

References 62 publications

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

Targeting of adenovirus vectors carrying a tumor cell-specific peptide: in vitro and in vivo studies

Development of a generic adenovirus delivery system based on structure-guided design of bispecific trimeric DARPin adapters

Recent developments in the use of adenoviruses and immunotoxins in cancer gene therapy

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