Institut für Molekulare Immunologie
TUM School of Medicine and Health
Technical University of Munich
Viral vectors for therapeutic approaches

We are generating different viral vectors with enhanced efficiency and selectivity for target cells or target organs. We design and produce a variety of recombinant viral vectors for potential therapeutic approaches, like tissue regeneration in bone and cartilage defects or as molecular biology tools to improve understanding of diseases. Our vector systems are based on adenovirus (Ad), adeno-associated virus (AAV), and retro- (RV) or lentivirus (LV). 

Optimization of viral vectors 

In order to minimize undesired side effects, we use regulated promoters that allow for switching on and off gene expression. To minimize immunogenicity, we investigate the use of polymers for shielding of virions. In a new scientific approach, we use different chemical as well as physical methods to enhance the transduction of primary cells and tissues. 

Viral vectors of bone and cartilage regeneration 

To address different needs and timing of gene expression of different tissues in the setting of osteoarthritis, we designed and investigated adenoviral vectors for regulated growth factor gene expression and assembled them with different biomaterials as scaffolds (EU-funded project „Gene Activated Matrices in Bone and cartilage regeneration in Arthritis“ (GAMBA) coordinated by PD Dr. Martina Anton. The project's aim was spatial as well as temporal control of gene expression of growth factors and/or cytokines to increase regeneration of bone, cartilage and reduce inflammation in degenerated joint tissues in the future. 

In an ongoing EU-funded project (Smart Bone Regeneration – SBR; https://www.smart-bone-regeneration.eu/), we design and optimize growth factors expressing AAV with the aim of enhancing bone regeneration in critical size bone defects. AAVs are combined with different biomaterials in order to localize gene transfer and reduce the immunogenicity of viral vectors. 

Viral vectors as molecular tools: tumor models, imaging

We developed (adeno) viral vectors for monitoring gene transfer to heart and tumors in vivo by non-invasive nuclear medical methods. 

PD Dr. Martina Anton was the first to describe an adenoviral vector expressing Cre recombinase, which allows for DNA recombination and induction of gene expression in vitro. Applied to mice with floxed sequences (e.g. lox-STOP-lox-Kras G12D), these Ad can be used to induce tumors without the need of breeding. We have used AdCre for organ-specific induction of lung and liver tumors in the respective transgenic mouse strains, which allow for the determination of genes involved in tumor development. These AdCre-induced tumors are optimal orthotopic tumor models, which can be used for further therapeutic interventions. 

In ongoing national and international collaborations, we stably transduce tumor cell lines and primary cells, with lentiviral vectors expressing reporter genes that allow for in vivo bioluminescence imaging for control of therapeutic interventions, long-term survival of transplanted cells in diverse animal models or ex vivo fluorescence imaging for identification of cells. 

Viral vectors delivering shRNAs and, most recently, CRISPR/Cas-mediated KO are used in diverse collaborative projects, allowing for analyses of the roles of different gene products in disease development.

PD Dr. Martina Anton
Research Group Leader
Institut für Molekulare Immunologie
Ismaninger Straße 22
81675 München
Contact: Research Group Anton:
Team
PD Dr. Martina Anton
PD Dr. Martina Anton
E-Mail +49 89 4140 4453
Ahmed Mousoski
Ahmed Mousoski
E-Mail +49 89 4140 4459
Eva Schmalzl
Eva Schmalzl
E-Mail +49 89 4140 4470
Dipl. Ing. FH Katja Dumler
Dipl. Ing. FH Katja Dumler
E-Mail +49 89 4140 4470
Publications

Original Publications (Key publications)

  1. Philippa Meiser, Moritz A. Knolle, Anna Hirschberger, Gustavo P. de Almeida, Felix Bayerl, Sebastian Lacher, Anna-Marie Pedde, Sophie Flommersfeld, Julian Hönninger, Leonhard Stark, Fabian Stögbauer, Martina Anton, Markus Wirth, Dirk Wohlleber, Katja Steiger, Veit R. Buchholz, Barbara Wollenberg, Christina E. Zielinski, Rickmer Braren, Daniel Rückert, Percy A. Knolle, Georgios Kaissisand Jan P. Böttcher. 2023. A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity. Accepted for publication in Cancer Cell.
  2. Felix Bayerl, Philippa Meiser, Sainitin Donakonda, Anna Hirschberger, Sebastian B. Lacher, Anna-Marie Pedde, Chris D. Hermann, Anais Elewaut, Moritz Knolle, Lukas Ramsauer, Thomas J. Rudolph, Simon Grassmann, Rupert Öllinger, Nicole Kirchhammer, Marcel Trefny, Martina Anton, Dirk Wohlleber, Bastian Höchst, Anne Zaremba, Achim Krüger, Roland Rad, Anna C. Obenauf, Dirk Schadendorf, Alfred Zippelius, Veit R. Buchholz, Barbara U. Schraml, Jan P. Böttcher. 2023.Tumor-derived prostaglandin E2 programs cDC1 dysfunction to impair intratumoral orchestration of anti-cancer T cell responses. Immunity 56: 1341-1358. DOI: doi.org/10.1016/j.immuni.2023.05.011. https://pubmed.ncbi.nlm.nih.gov/37315536/
  3. Adam Wahida, Madeleine Müller, Andreas Hiergeist, Bastian Popper, Katja Steiger, Caterina Branca, Markus Tschurtschenthaler, Thomas Engleitner, Sainitin Donakonda, Jordy De Coninck, Rupert Öllinger, Marie K. Pfautsch, Nicole Müller, Miguel Silva, Sinem Usluer, Jan P. Böttcher, Nicole Pfarr, Martina Anton, Julia B. Slotta-Huspenina, Andreas G. Nerlich, Tobias Madl, Marijana Basic, André Bleich, Geert Berx, Jürgen Ruland, Percy A. Knolle, Roland Rad, Timon E. Adolph, Peter Vandenabeele, Hirokazu Kanegane, André Gessner, Philipp J. Jost, Monica Yabal. 2021. XIAP restrains TNF-driven intestinal inflammation and dysbiosis by promoting appropriate immune responses of Paneth and dendritic cells. Science Immunology 6(65): eabf7235. DOI: 10.1126/sciimmunol.abf7235. https://pubmed.ncbi.nlm.nih.gov/34739338/
  4. Michael Dudek, Dominik Pfister, Sainitin Donakonda, Pamela Filpe, Annika Schneider, Melanie Laschinger, Daniel Hartmann, Norbert Hüser, Philippa Meiser, Felix Bayerl, Donato Inverso, Jennifer Wigger, Marcial Sebode, Rupert Öllinger, Roland Rad, Silke Hegenbarth, Martina Anton, Adrien Guillot, Andrew Bowman, Danijela Heide, Florian Müller, Pierluigi Ramadori, Valentina Leone, Cristina Garcia-Caceres, Tim Gruber, Gabriel Seifert, Agnieszka M. Kabat, Jan-Philipp Mallm, Simon Reider, Maria Effenberger, Susanne Roth, Adrian T. Billeter, Beat Müller-Stich, Edward J. Pearce, Friedrich Nolte-Koch, Rafael Käser, Herbert Tilg, Robert Thimme, Tobias Boettler, Frank Tacke, Jean-Francois Dufour, Dirk Haller, Peter Murray, Ron Heeren, Dietmar Zehn, Jan Böttcher, Mathias Heikenwälder, Percy A. Knolle. 2021. Auto-aggressive CXCR6+ CD8 T cells cause liver immune pathology in NASH. Nature 592(7854): 444-449. DOI: 10.1038/s41586-021-03233-8. https://www.nature.com/articles/s41586-021-03233-8
  5. Enkhtsetseg Munkhbaatar, Michelle Dietzen, Deepti Agrawal, Martina Anton, Moritz Jesinghaus, Melanie Boxberg, Nicole Pfarr, Pidassa Bidola, Sebastian Uhrig, Ulrike Höckendorf, Anna-Lena Meinhard, Adam Wahida, Irina Heid, Rickmer Braren, Ritu Mishra, Arne Warth, Thomas Muley, Patrina S.P. Poh, Xin Wang, Stefan Fröhling, Katja Steiger, Julia Slotta-Huspenina, Martijn van Griensven, Franz Pfeiffer, Sebastian Lange, Roland Rad, Magda Spella, Gergious T. Stathopoulos , Jürgen Ruland, Florian Bassermann, Wilko Weichert, Andreas Strasser, Caterine Branca, Mathias Heikenwälder, Charles Swanton, Nicholas McGranahan, Philipp J. Jost. 2020. MCL-1 gains occur with high frequency in lung adenocarcinoma and can be targeted therapeutically. Nature Communications 11(1): 4527. DOI: 10.1038/s41467-020-18372-1. https://www.nature.com/articles/s41467-020-18372-1
  6. Alexander Taschauer, Wolfram Polzer, Stefan Pöschl, Slavica Metz, Nathalie Tepe, Simon Decker, Norbert Cyran, Julia Scholda, Julia Maier, Hermann Blos, Martina Anton, Thilo Hofmann, Manfred Ogris, Haider Sami. 2020. Combined chemisorption and complexation generates siRNA nanocarrriers with biophysics optimized for efficient gene-knockdown and air-blood barrier crossing. ACS Applied Materials & Interfaces. 12(27): 30095-30111. DOI: 10.1021/acsami.0c06608. https://pubmed.ncbi.nlm.nih.gov/32515194/
  7. Meike Welz, Sarah Eickhoff, Zeinab Abdullah, Jonel Trebicka, Kate H. Gartlan, Julie A. Spicer, Anthony J. Demetris, Hedieh Akhlaghi, Martina Anton, Katrin Manske, Dietmar Zehn, Bernhard Nieswandt, Christian Kurts, Joseph A. Trapani, Percy Knolle, Dirk Wohlleber, Wolfgang Kastenmüller. 2018. Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis. Nature Commun. 9(1): 4805. DOI: 10.1038/s41467-07213-x. https://pubmed.ncbi.nlm.nih.gov/30442932/
  8. Jennifer J. Bara, Iska Dresing, Stephan Zeiter, Martina Anton, Guy Daculsi, David Eglin, Dirk Nehrbass, Vincent A. Stadelmann, Duncan C Betts, Ralph Müller, Mauro Alini, Martin J. Stoddart. 2018. A doxycycline inducible, adenoviral BMP-2 gene delivery system to bone. J. Tissue Eng. Reg. Med. 12(1): e106-e118. DOI: 10.1002/term.2393. https://pubmed.ncbi.nlm.nih.gov/27957814/
  9. Yvonn Heun, Staffan Hildebrand, Alexandra Heidsieck, Bernhard Gleich, Martina Anton, Joachim Pircher, Andrea Ribeiro, Olga Mykhaylyk, Dietmar Eberbeck, Daniela Wenzel, Alexander Pfeifer, Markus Woernle, Florian Krötz, Ulrich Pohl, Hanna Mannell. 2017. Targeting of Magnetic Nanoparticle-coated microbubbles to the Vascular Wall Empowers Site-specific Lentiviral Gene Delivery in vivo. Theranostics. 7(2): 295-307. DOI: 10.7150/thno.16192. https://pubmed.ncbi.nlm.nih.gov/28042335/
  10. Youlia Kostova, Klaus Mantwill, Per S. Holm, Martina Anton. 2015. An armed, YB-1 dependent oncolytic adenovirus as a candidate for a combinatorial anti-glioma approach of virotherapy, suicide gene therapy and chemotherapeutic treatment. Cancer Gene Therapy. 22(1): 30-43. [Epub ahead of print 12.12.2014]. DOI: 10.1038/cgt.2014.67 https://pubmed.ncbi.nlm.nih.gov/25501992/
  11. Anja Baumgart, Pawel Mazur, Martina Anton, Martina Rudelius, Kristina Schwamborn, Annette Feuchtinger, Kerstin Behnke, Axel Walch, Rickmer Braren, Christian Peschel, Justus Duyster, Jens T. Siveke, Tobias Dechow. 2015. Opposing role of Notch1 and Notch2 in a KrasG12D-driven murine non-small cell lung cancer model. Oncogene. 34(5): 578-88. [Epub ahead of print 10.02.2014]. doi: 10.1038/onc.2013.592. https://pubmed.ncbi.nlm.nih.gov/24509876/
  12. Christian Plank, David Eglin, Niamh Fahy, Cedric Sapet, Pascal Borget, Gerjo van Osch, Rui Pereira, Thomas Miramond, Katharina Zöller, Martina Anton. 2012. Gene Activated Matrices for Bone and Cartilage Regeneration in Arthritis. GAMBA – an EU-Funded Project. Eur. J. Nanomed. 4(1):17–32 https://www.degruyter.com/document/doi/10.1515/ejnm-2012-0001/html
  13. Martina Anton, Anja Wolf, Olga Mykhaylyk, Christian Koch, Bernd Gansbacher, Christian Plank. 2012. Optimizing Adenoviral transduction of endothelial cells under flow conditions. Pharm. Res. 29(5): 1219-1231. DOI 10.1007/s11095-011-0631-2 [epub ahead of print Dec 30th 2011] https://pubmed.ncbi.nlm.nih.gov/22207207/
  14. Yolanda Sanchez Antequera, Olga Mykhaylyk, Arzu Cengizeroglu, Niek P van Til, Martina Anton, Ian CD Johnston, Zygmunt Pojda, Gerard Wagemaker, Christian Plank. 2011. Genetic modification of cells on a separation column modified with magnetic gene delivery vectors: Magselectofection. Blood 117(16): e171-181. [Epub ahead of print February 28, 2011; DOI 10.1182/blood-2010-08-302646]. https://www.sciencedirect.com/science/article/pii/S0006497120452577
  15. Daniela Wübbenhorst, Bettina Wagner, Katja Dumler, Gabriele Wexel, Andreas Imhoff, Bernd Gansbacher, Stephan Vogt, Martina Anton. 2010. Tet-regulated BMP-2 gene expression in lentivirally transduced primary rabbit chondrocytes. [Epub ahead of print 2010 Mar 22. DOI 10.1002/art.27461]. Arthritis & Rheumatism 62(7): 2037–2046. https://pubmed.ncbi.nlm.nih.gov/20309869/
  16. Martina Anton, Iman E.O. Gomaa, Tobias v. Lukowicz, Michael Molls, Bernd Gansbacher, Florian Würschmidt. 2005. Optimization of radiation controlled gene expression by adenoviral vectors in vitro. Cancer Gene Therapy advance online publication, 1 April 2005; doi:10.1038/sj.cgt.7700829. Cancer Gene Therapy 12 (7): 640-646. https://www.nature.com/articles/7700829
  17. Frank M. Bengel, Martina Anton, Thomas Richter, Marcus V. Simoes, Roland Haubner, Julia Henke, Wolf Erhardt, Sybille Reder, Terry Lehner, Wolfgang Brandau, Peter Boekstegers, Stephan G. Nekolla, Bernd Gansbacher, and Markus Schwaiger. 2003. Noninvasive imaging of transgene expression by use of positron emission tomography in a pig model of myocardial gene transfer. Circulation 108: 2127- 2133. https://pubmed.ncbi.nlm.nih.gov/14530205/
  18. Franz Scherer*, Martina Anton*, Ulrike Schillinger, Julia Henke, Christian Bergemann, Achim Krüger, Bernd Gansbacher, and Christian Plank. 2002. Magnetofection: Enhancing and targeting gene delivery by magnetic force in vitro and in vivo. Gene Therapy 9: 102-109. (* equal contribution) https://pubmed.ncbi.nlm.nih.gov/11857068/
  19. Robin J. Parks, Liane Chen, Martina Anton, Uma Sankar, Michael A. Rudnicki, and Frank L. Graham. 1996. A new helper-dependent adenovirus vector system: removal of helper virus by Cre mediated excision of the viral packaging signal. Proc. Natl. Acad. Sci. USA 93: 13565-13570. https://www.pnas.org/doi/10.1073/pnas.93.24.13565
  20. Martina Anton and Frank L. Graham. 1995. Site-specific recombination mediated by an adenovirus vector expressing the Cre recombinase protein: a molecular switch for control of gene expression. J. Virology 69: 4600-4606. https://pubmed.ncbi.nlm.nih.gov/7609024/

 

Book Chapters

 Martina Anton, Bernd Gänsbacher. 2012. Tumor imaging with adenoviral vectors. The CliniBook: Clinical gene transfer. ed. Odile Cohen-Haguenauer, EDK Paris: 155-158.

Olga Mykhaylyk, Olivier Zelphati, Edelbuga Hammerschmid, Martina Anton, Joseph Rosenegger, Christian Plank. 2009. Recent advances in magnetofection and its potential to deliver siRNAs in vitro. Methods Mol Biol. 487: 111-146.

Olga Mykhaylyk, Yolanda Sánchez Antequera, Dialekti Vlaskou, Edelburga Hammerschmid, Martina Anton, Olivier Zelphati, Christian Plank. 2009. Liposomal Magnetofection. Methods in Molecular Biology 605: 487-525. DOI 10.1007/978-1-60327-360-2_34.

The full list of our publications can be found here on Pubmed.

Funding

Smart bone Repair (SBR) has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No. 874896. ; https://www.smart-bone-regeneration.eu/

We acknowledge previous funding was by EU, DFG, BMBF