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Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer.

Authors
  • Finet, J Emanuel1
  • Wan, Xiaoping2
  • Donahue, J Kevin3
  • 1 Krannert Institute of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, USA. , (India)
  • 2 Heart and Vascular Research Center, Case Western Reserve University, MetroHealth Campus, Cleveland, OH, USA.
  • 3 Division of Cardiology, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, 7th floor, Worcester, MA 01605, USA. Electronic address: [email protected]
Type
Published Article
Journal
Virology
Publisher
Elsevier
Publication Date
Jan 01, 2018
Volume
513
Pages
43–51
Identifiers
DOI: 10.1016/j.virol.2017.10.006
PMID: 29032346
Source
Medline
Keywords
License
Unknown

Abstract

AAV-mediated gene therapy has become a promising therapeutic strategy for chronic diseases. Its clinical utilization, however, is limited by the potential risk of off-target effects. In this work we attempt to overcome this challenge, hypothesizing that cardiac ion channel-specific ligands could be fused onto the AAV capsid, and narrow its tropism to cardiac myocytes. We successfully fused the cardiac sodium channel (Nav1.5)-binding toxin Anthopleurin-B onto the AAV2 capsid without compromising virus integrity, and demonstrated increased specificity of cardiomyocyte attachment. Although virus attachment to Nav1.5 did not supersede the natural heparan-mediated virus binding, heparan-binding ablated vectors carrying Anthopleurin-B eliminated hepatic and other extracardiac gene transfer, while preserving cardiac myocyte gene transfer. Virus binding to the cardiac sodium channel transiently decreased sodium current density, but did not cause any arrhythmias. Our findings expand the knowledge of attachment, infectivity, and intracellular processing of AAV vectors, and present an alternative strategy for vector retargeting.

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