期刊
MOLECULAR THERAPY
卷 27, 期 3, 页码 611-622出版社
CELL PRESS
DOI: 10.1016/j.ymthe.2019.01.015
关键词
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资金
- NIH [R21HL126053, R01HL138126, R01CA207497, R01GM082946, S10 OD018142-01, S10 RR025080-01, U24 GM116788]
- American Heart Association [13GRNT14420044, 15GRNT23070007, 16PRE30690006]
- Dunn Foundation
- National Science Foundation [2015197891, 2018253392]
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.
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