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Mol Ther. 2019 Mar 6;27(3):611-622. doi: 10.1016/j.ymthe.2019.01.015. Epub 2019 Jan 29.

Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue.

Author information

1
Department of Bioengineering, Rice University, 6100 Main St., Houston, TX 77005, USA.
2
Department of Chemical and Biomolecular Engineering, Rice University, 6100 Main Street, Houston, TX 77005, USA.
3
Department of Biochemistry and Molecular Biology, University of Florida, 1200 Newell Drive, Gainesville, FL 32610, USA.
4
Institute of Molecular Medicine, University of Texas Health Science Center at Houston, 6767 Bertner Avenue, Houston, TX 77225, USA.
5
Biological Science Imaging facility (BSIR), Department of Biology, 89 Chieftan Way, Florida State University, Tallahassee, FL 32306, USA.
6
Department of Bioengineering, Rice University, 6100 Main St., Houston, TX 77005, USA. Electronic address: jsuh@rice.edu.

Abstract

Adeno-associated virus (AAV) has emerged as a promising gene delivery vector because of its non-pathogenicity, simple structure and genome, and low immunogenicity compared to other viruses. However, its adoption as a safe and effective delivery vector for certain diseases relies on altering its tropism to deliver transgenes to desired cell populations. To this end, we have developed a protease-activatable AAV vector, named provector, that responds to elevated extracellular protease activity commonly found in diseased tissue microenvironments. The AAV9-based provector is initially inactive, but then it can be switched on by matrix metalloproteinases (MMP)-2 and -9. Cryo-electron microscopy and image reconstruction reveal that the provector capsid is structurally similar to that of AAV9, with a flexible peptide insertion at the top of the 3-fold protrusions. In an in vivo model of myocardial infarction (MI), the provector is able to deliver transgenes site specifically to high-MMP-activity regions of the damaged heart, with concomitant decreased delivery to many off-target organs, including the liver. The AAV provector may be useful in the future for enhanced delivery of transgenes to sites of cardiac damage.

KEYWORDS:

AAV; activatable; adeno-associated virus; cardiac gene therapy; gene delivery; gene therapy; inflammation targeting; matrix metalloproteinase; myocardial infarction; provector; stimulus responsive; viral vector

PMID:
30772143
PMCID:
PMC6404099
[Available on 2020-03-06]
DOI:
10.1016/j.ymthe.2019.01.015

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