AAV-mediated in vivo functional selection of tissue-protective factors against ischaemia

Giulia Ruozi, Francesca Bortolotti, Antonella Falcione, Matteo Dal Ferro, Laura Ukovich, Antero Macedo, Lorena Zentilin, Nicoletta Filigheddu, Gianluca Gortan Cappellari, Giovanna Baldini, Marina Zweyer, Rocco Barazzoni, Andrea Graziani, Serena Zacchigna and Mauro Giacca ()
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Giulia Ruozi: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Francesca Bortolotti: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Antonella Falcione: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Matteo Dal Ferro: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Laura Ukovich: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Antero Macedo: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Lorena Zentilin: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Nicoletta Filigheddu: University of Piemonte Orientale ‘A. Avogadro’
Gianluca Gortan Cappellari: Surgical and Health Sciences, University of Trieste
Giovanna Baldini: Surgical and Health Sciences, University of Trieste
Marina Zweyer: Surgical and Health Sciences, University of Trieste
Rocco Barazzoni: Surgical and Health Sciences, University of Trieste
Andrea Graziani: University of Piemonte Orientale ‘A. Avogadro’
Serena Zacchigna: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)
Mauro Giacca: Molecular Medicine Laboratory, International Centre for Genetic Engineering and Biotechnology (ICGEB)

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract Functional screening of expression libraries in vivo would offer the possibility of identifying novel biotherapeutics without a priori knowledge of their biochemical function. Here we describe a procedure for the functional selection of tissue-protective factors based on the in vivo delivery of arrayed cDNA libraries from the mouse secretome using adeno-associated virus (AAV) vectors. Application of this technique, which we call FunSel, in the context of acute ischaemia, revealed that the peptide ghrelin protects skeletal muscle and heart from ischaemic damage. When delivered to the heart using an AAV9 vector, ghrelin markedly reduces infarct size and preserves cardiac function over time. This protective activity associates with the capacity of ghrelin to sustain autophagy and remove dysfunctional mitochondria after myocardial infarction. Our findings describe an innovative tool to identify biological therapeutics and reveal a novel role of ghrelin as an inducer of myoprotective autophagy.

Date: 2015
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DOI: 10.1038/ncomms8388

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