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TitleProtease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue.
Journal, issue, pagesMol Ther, Vol. 27, Issue 3, Page 611-622, Year 2019
Publish dateMar 6, 2019
AuthorsCaitlin M Guenther / Mitchell J Brun / Antonette D Bennett / Michelle L Ho / Weitong Chen / Banghe Zhu / Michael Lam / Momona Yamagami / Sunkuk Kwon / Nilakshee Bhattacharya / Duncan Sousa / Annicka C Evans / Julie Voss / Eva M Sevick-Muraca / Mavis Agbandje-McKenna / Junghae Suh /
PubMed AbstractAdeno-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, ...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.
External linksMol Ther / PubMed:30772143 / PubMed Central
MethodsEM (single particle)
Resolution3.16 Å
Structure data

0535

6nxe

EMDB-0535, PDB-6nxe:
Cryo-EM Reconstruction of Protease-Activateable Adeno-Associated Virus 9 (AAV9-L001)
Method: EM (single particle) / Resolution: 3.16 Å

Source
  • adeno-associated virus
KeywordsVIRUS / AAV / activatable / gene therapy / provector

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