Pulmonary Targeting of Adeno-associated Viral Vectors by Next-generation Sequencing-guided Screening of Random Capsid Displayed Peptide Libraries

Jakob Körbelin, Timo Sieber, Stefan Michelfelder, Lars Lunding, Elmar Spies, Agnes Hunger, Malik Alawi, Kleopatra Rapti, Daniela Indenbirken, Oliver J. Müller, Renata Pasqualini, Wadih Arap, Jürgen A. Kleinschmidt, Martin Trepel

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Vectors mediating strong, durable, and tissue-specific transgene expression are mandatory for safe and effective gene therapy. In settings requiring systemic vector administration, the availability of suited vectors is extremely limited. Here, we present a strategy to select vectors with true specificity for a target tissue from random peptide libraries displayed on adeno-associated virus (AAV) by screening the library under circulation conditions in a murine model. Guiding the in vivo screening by next-generation sequencing, we were able to monitor the selection kinetics and to determine the right time point to discontinue the screening process. The establishment of different rating scores enabled us to identify the most specifically enriched AAV capsid candidates. As proof of concept, a capsid variant was selected that specifically and very efficiently delivers genes to the endothelium of the pulmonary vasculature after intravenous administration. This technical approach of selecting target-specific vectors in vivo is applicable to any given tissue of interest and therefore has broad implications in translational research and medicine.

Original languageEnglish (US)
Pages (from-to)1050-1061
Number of pages12
JournalMolecular Therapy
Volume24
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

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

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