کد مقاله کد نشریه سال انتشار مقاله انگلیسی نسخه تمام متن
5674815 1594204 2018 9 صفحه PDF دانلود رایگان
عنوان انگلیسی مقاله ISI
Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer
موضوعات مرتبط
علوم زیستی و بیوفناوری ایمنی شناسی و میکروب شناسی ویروس شناسی
پیش نمایش صفحه اول مقاله
Fusion of Anthopleurin-B to AAV2 increases specificity of cardiac gene transfer
چکیده انگلیسی


- 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.

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.

ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Virology - Volume 513, 1 January 2018, Pages 43-51
نویسندگان
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