Systemic Vascular Transduction by Capsid Mutant Adeno-Associated Virus after Intravenous Injection

Daniel M. Lipinski, Chris A. Reid, Sanford L. Boye, James J. Peterson, Xiaoping Qi, Shannon E. Boye, Michael E. Boulton, William W. Hauswirth

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

The ability to effectively deliver genetic material to vascular endothelial cells remains one of the greatest unmet challenges facing the development of gene therapies to prevent diseases with underlying vascular etiology, such as diabetes, atherosclerosis, and age-related macular degeneration. Herein, we assess the effectiveness of an rAAV2-based capsid mutant vector (Y272F, Y444F, Y500F, Y730F, T491V; termed QuadYF+TV) with strong endothelial cell tropism at transducing the vasculature after systemic administration. Intravenous injection of QuadYF+TV resulted in widespread transduction throughout the vasculature of several major organ systems, as assessed by in vivo bioluminescence imaging and postmortem histology. Robust transduction of lung tissue was observed in QuadYF+TV-injected mice, indicating a role for intravenous gene delivery in the treatment of chronic diseases presenting with pulmonary complications, such as α1-Antitrypsin deficiency. The QuadYF+TV vector cross-reacted strongly with AAV2 neutralizing antibodies, however, indicating that a targeted delivery strategy may be required to maximize clinical translatability.

Original languageEnglish (US)
Pages (from-to)767-776
Number of pages10
JournalHuman gene therapy
Volume26
Issue number11
DOIs
StatePublished - Nov 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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    Lipinski, D. M., Reid, C. A., Boye, S. L., Peterson, J. J., Qi, X., Boye, S. E., Boulton, M. E., & Hauswirth, W. W. (2015). Systemic Vascular Transduction by Capsid Mutant Adeno-Associated Virus after Intravenous Injection. Human gene therapy, 26(11), 767-776. https://doi.org/10.1089/hum.2015.097