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Modular adeno-associated virus (rAAV) vectors used for cellular virus-directed enzyme prodrug therapy

  • The pre-clinical and clinical development of viral vehicles for gene transfer increased in recent years, and a recombinant adeno-associated virus (rAAV) drug took center stage upon approval in the European Union. However, lack of standardization, inefficient purification methods and complicated retargeting limit general usability. We address these obstacles by fusing rAAV-2 capsids with two modular targeting molecules (DARPin or Affibody) specific for a cancer cell-surface marker (EGFR) while simultaneously including an affinity tag (His-tag) in a surface-exposed loop. Equipping these particles with genes coding for prodrug converting enzymes (thymidine kinase or cytosine deaminase) we demonstrate tumor marker specific transduction and prodrug-dependent apoptosis of cancer cells. Coding terminal and loop modifications in one gene enabled specific and scalable purification. Our genetic parts for viral production adhere to a standardized cloning strategy facilitating rapid prototyping of virus directed enzyme prodrug therapy (VDEPT).

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Author:Sven Hagen, Tobias BaumannORCiD, Hanna J. Wagner, Volker Morath, Beate Kaufmann, Adrian Fischer, Stefan Bergmann, Patrick Schindler, Katja Maren ArndtORCiDGND, Kristian M. Mueller
ISSN:2045-2322 (print)
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=24457557
Parent Title (English):Scientific reports
Publisher:Nature Publ. Group
Place of publication:London
Document Type:Article
Year of first Publication:2014
Year of Completion:2014
Release Date:2017/03/27
Funder:Excellence Initiative of the German Federal and State Governments [EXC 294]; DFG [SPP1170]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie
Peer Review:Referiert
Publication Way:Open Access