Autophagic and Epigenetic Control of Liver-Directed Gene Therapy with Adeno-Associated Viral Vectors

• Applicants: Professorin Dr. Hildegard Büning; Professorin Dr. Margarete Odenthal
• Subject Area: Gastroenterology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431535912

• Final Report Year: 2024

Final Report Abstract

In the present project, we focused on two aspects of the adeno-associated virus (AAV) vectorhost interaction that are expected to have major implications for the application of AAV vectors in gene therapy. Based on our previous work showing that autophagy significantly increases the efficiency of AAV vector-mediated transgene expression, we first investigated liver-specific autophagy and epigenetically mediated mechanisms of AAV vector genome transcription. We show that activation and nuclear transduction of HNF1α is crucial for transgene expression. Our investigation on HNF1α binding and histone modification of regions adjacent to the AAV serotype 2 (AAV2) inverted terminal repeats (ITRs), which functions as liver-specific enhancer domain, provides primary evidence that histone modification, but not the site-specific HNF1α interaction is involved in enhancement of transgene transcription. In a second approach, we investigated IL-6 / autophagy signaling in hepatocytes in response to Toll-Like Receptor (TLR) 2-mediated recognition of AAV vectors. Importantly, in agreement to our previous work, the IL-6 /autophagy axis leads to increased transgene expression efficiency, whereas inhibition of the IL-6 signal transducing mediator, STAT3, decreased autophagy and reduced transgene expression. Furthermore, we demonstrated that administration of recombinant IL-6 resulted in elevated transduction efficiency of AAV vectors in primary human hepatocytes in vitro and in C57BL/6 mice in vivo. These results are prepared for publication.

Publications

• Adeno-associated virus (AAV) capsid engineering in liver-directed gene therapy. Expert Opinion on Biological Therapy, 1-18.
  Rodríguez-Márquez, Esther; Meumann, Nadja & Büning, Hildegard
  
• Autophagy-Related Activation of Hepatic Stellate Cells Reduces Cellular miR-29a by Promoting Its Vesicular Secretion. Cellular and Molecular Gastroenterology and Hepatology, 13(6), 1701-1716.
  Yu, Xiaojie; Elfimova, Natalia; Müller, Marion; Bachurski, Daniel; Koitzsch, Ulrike; Drebber, Uta; Mahabir, Esther; Hansen, Hinrich P.; Friedman, Scott L.; Klein, Sabine; Dienes, Hans Peter; Hösel, Marianna; Buettner, Reinhard; Trebicka, Jonel; Kondylis, Vangelis; Mannaerts, Inge & Odenthal, Margarete
  
• Hepatocellular Carcinoma Is a Natural Target for Adeno-Associated Virus (AAV) 2 Vectors. Cancers, 14(2), 427.
  Meumann, Nadja; Schmithals, Christian; Elenschneider, Leroy; Hansen, Tanja; Balakrishnan, Asha; Hu, Qingluan; Hook, Sebastian; Schmitz, Jessica; Bräsen, Jan Hinrich; Franke, Ann-Christin; Olarewaju, Olaniyi; Brandenberger, Christina; Talbot, Steven R.; Fangmann, Josef; Hacker, Ulrich T.; Odenthal, Margarete; Ott, Michael; Piiper, Albrecht & Büning, Hildegard
  
• Adeno‐associated virus serotype 2 capsid variants for improved liver‐directed gene therapy. Hepatology, 77(3), 802-815.
  Meumann, Nadja; Cabanes‐Creus, Marti; Ertelt, Moritz; Navarro, Renina Gale; Lucifora, Julie; Yuan, Qinggong; Nien‐Huber, Karin; Abdelrahman, Ahmed; Vu, Xuan‐Khang; Zhang, Liang; Franke, Ann‐Christin; Schmithals, Christian; Piiper, Albrecht; Vogt, Annabelle; Gonzalez‐Carmona, Maria; Frueh, Jochen T.; Ullrich, Evelyn; Meuleman, Philip; Talbot, Steven R. ... & Büning, Hildegard