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Virology v.513, 2018년, pp.43 - 51   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

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

Finet, J. Emanuel    (Krannert Institute of Cardiology, Department of Medicine, Indiana University, Indianapolis, IN, USA   ); Wan, Xiaoping    (Heart and Vascular Research Center, Case Western Reserve University, MetroHealth Campus, Cleveland, OH, USA   ); Donahue, J. Kevin    (Division of Cardiology, Department of Medicine, University of Massachusetts Medical School, 368 Plantation Street, Albert Sherman Center, 7th floor, Worcester, MA 01605, USA  );
  • 초록  

    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 (Na v 1.5)-binding toxin Anthopleurin-B onto the AAV2 capsid without compromising virus integrity, and demonstrated increased specificity of cardiomyocyte attachment. Although virus attachment to Na v 1.5 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. Highlights The AAV2 capsid can accommodate insertion of the sodium channel binding toxin ApB. ApB-AAV2 blocks sodium current indicating that it accessible from the outside of the virus and that it retains channel binding capacity. Intracellular processing of ApB-AAV2 did not differ significantly from AAV2. ApB insertion and heparan sulfate binding deletion in AAV2 led to a virus with increased specificity of cardiac myocyte attachment in vivo in rats.


  • 주제어

    AAV .   Nav1.   5 .   Anthopleurin-B .   Cardiomyocyte .   Retargeting .   Specificity .   Attachment.  

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