Capsid Engineering Overcomes Barriers Toward Adeno-Associated Virus Vector-Mediated Transduction of Endothelial Cells

L Zhang, A Rossi, L Lange, N Meumann, U Koitzsch, Kathleen Christie, M. Andrew Nesbit, Tara C. B. Moore, U.T. Hacker, M. Morgan, D. Hoffmann, James Zengel, Jan E. Carette, A. Schambach, A. Salvetti, Margarete Odenthal, Hildegard Büning

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Abstract

Endothelial cells (EC) are targets in gene therapy and regenerative medicine, but they are inefficiently transduced with adeno-associated virus (AAV) vectors of various serotypes. To identify barriers hampering efficient transduction and to develop an optimized AAV variant for EC transduction, we screened an AAV serotype 2-based peptide display library on primary human macrovascular EC. Using a new high-throughput selection and monitoring protocol, we identified a capsid variant, AAV-V EC, which outperformed the parental serotype as well as first-generation targeting vectors in EC transduction. AAV vector uptake was improved, resulting in significantly higher transgene expression levels from single-stranded vector genomes detectable within a few hours post-transduction. Notably, AAV-V EC transduced not only proliferating EC but also quiescent EC, although higher particle-per-cell ratios had to be applied. Also, induced pluripotent stem cell-derived endothelial progenitor cells, a novel tool in regenerative medicine and gene therapy, were highly susceptible toward AAV-V EC transduction. Thus, overcoming barriers by capsid engineering significantly expands the AAV tool kit for a wide range of applications targeting EC.

Original languageEnglish
Pages (from-to)1284-1296
Number of pages13
JournalHuman Gene Therapy
Volume30
Issue number10
Early online date13 Aug 2019
DOIs
Publication statusPublished - 23 Sep 2019

Keywords

  • AAV vectors
  • endothelial cells
  • induced pluripotent stem cells
  • uncoating
  • uptake

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    Zhang, L., Rossi, A., Lange, L., Meumann, N., Koitzsch, U., Christie, K., Nesbit, M. A., Moore, T. C. B., Hacker, U. T., Morgan, M., Hoffmann, D., Zengel, J., Carette, J. E., Schambach, A., Salvetti, A., Odenthal, M., & Büning, H. (2019). Capsid Engineering Overcomes Barriers Toward Adeno-Associated Virus Vector-Mediated Transduction of Endothelial Cells. Human Gene Therapy, 30(10), 1284-1296. https://doi.org/10.1089/hum.2019.027