Universität zu Köln

Hoesel, Marianna, Huber, Anke, Bohlen, Susanne, Lucifora, Julie, Ronzitti, Giuseppe, Puzzo, Francesco, Boisgerault, Florence, Hacker, Ulrich T., Kwanten, Wilhelmus J., Kloeting, Nora, Blueher, Matthias, Gluschko, Alexander, Schramm, Michael, Utermoehlen, Olaf, Bloch, Wilhelm, Mingozzi, Federico, Krut, Oleg and Buening, Hildegard (2017). Autophagy Determines Efficiency of Liver-Directed Gene Therapy With Adeno-Associated Viral Vectors. Hepatology, 66 (1). S. 252 - 266. HOBOKEN: WILEY. ISSN 1527-3350

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Abstract

Use of adeno-associated viral (AAV) vectors for liver-directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)-dependent autophagy in human hepatocytes. This cell response was critically required for efficient transduction because under conditions of impaired autophagy (pharmacological inhibition, small interfering RNA knockdown of autophagic proteins, or suppression by food intake), recombinant AAV-mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependence, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter, or AAV serotype and was subsequently confirmed in vivo. Specifically, short-term treatment with a single dose of torin 1 significantly increased vector-mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, coadministration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid-alpha-glucosidase in nonhuman primates. Conclusion: We identified autophagy as a pivotal cell response determining the efficiency of AAVs intracellular processing in hepatocytes and thus the outcome of liver-directed gene therapy using AAV vectors and showed in a proof-of-principle study how this virus-host interaction can be employed to enhance efficacy of this vector system.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoesel, Marianna UNSPECIFIED UNSPECIFIED UNSPECIFIED Huber, Anke UNSPECIFIED UNSPECIFIED UNSPECIFIED Bohlen, Susanne UNSPECIFIED UNSPECIFIED UNSPECIFIED Lucifora, Julie UNSPECIFIED UNSPECIFIED UNSPECIFIED Ronzitti, Giuseppe UNSPECIFIED UNSPECIFIED UNSPECIFIED Puzzo, Francesco UNSPECIFIED UNSPECIFIED UNSPECIFIED Boisgerault, Florence UNSPECIFIED UNSPECIFIED UNSPECIFIED Hacker, Ulrich T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kwanten, Wilhelmus J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kloeting, Nora UNSPECIFIED UNSPECIFIED UNSPECIFIED Blueher, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Gluschko, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Schramm, Michael UNSPECIFIED UNSPECIFIED UNSPECIFIED Utermoehlen, Olaf UNSPECIFIED UNSPECIFIED UNSPECIFIED Bloch, Wilhelm UNSPECIFIED UNSPECIFIED UNSPECIFIED Mingozzi, Federico UNSPECIFIED UNSPECIFIED UNSPECIFIED Krut, Oleg UNSPECIFIED UNSPECIFIED UNSPECIFIED Buening, Hildegard UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-226628
DOI:	10.1002/hep.29176
Journal or Publication Title:	Hepatology
Volume:	66
Number:	1
Page Range:	S. 252 - 266
Date:	2017
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1527-3350
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEPATIC LIPID-METABOLISM; MAMMALIAN TARGET; HEMOPHILIA-B; IN-VITRO; VIRUS; RAPAMYCIN; MTOR; TRANSDUCTION; DISEASES; CANCER Multiple languages Gastroenterology & Hepatology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22662