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

Caitlin 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

Research output: Contribution to journalArticle

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. Guenther et al. have developed a protease-activatable AAV provector to target diseased tissue microenvironments exhibiting elevated extracellular protease activity. The provector delivers transgenes to high-MMP-activity regions of the damaged heart following a myocardial infarction, with concomitant decreased delivery to many off-target organs, including the liver.

Original languageEnglish (US)
JournalMolecular Therapy
DOIs
StatePublished - Jan 1 2019
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Guenther, C. M., Brun, M. J., Bennett, A. D., Ho, M. L., Chen, W., Zhu, B., Lam, M., Yamagami, M., Kwon, S., Bhattacharya, N., Sousa, D., Evans, A. C., Voss, J., Sevick-Muraca, E. M., Agbandje-McKenna, M., & Suh, J. (2019). Protease-Activatable Adeno-Associated Virus Vector for Gene Delivery to Damaged Heart Tissue. Molecular Therapy. https://doi.org/10.1016/j.ymthe.2019.01.015