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


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.

SUBMITTER: Guenther CM 

PROVIDER: S-EPMC6404099 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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

Guenther Caitlin M CM   Brun Mitchell J MJ   Bennett Antonette D AD   Ho Michelle L ML   Chen Weitong W   Zhu Banghe B   Lam Michael M   Yamagami Momona M   Kwon Sunkuk S   Bhattacharya Nilakshee N   Sousa Duncan D   Evans Annicka C AC   Voss Julie J   Sevick-Muraca Eva M EM   Agbandje-McKenna Mavis M   Suh Junghae J  

Molecular therapy : the journal of the American Society of Gene Therapy 20190129 3


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 comm  ...[more]

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