Lecture prof. Merkel and Lamb

(29-11-2019)

                                                                                            FWO Research Consortium

                                                                                              LECTURE INVITATION

11:00am    Pulmonary siRNA Delivery for the Treatment of Asthma and other Diseases
                  Prof. Olivia Merkel, LMU Munich
11:30am    From dancing proteins to running mitochondria: Elucidating the dynamics of life using fluorescence
                  Prof. Don Lamb, LMU Munich

The seminar will take place on Monday 16th of December in Seminar Room 2 at the faculty of pharmaceutical sciences, Ottergemse steenweg 460, 9000 Ghent, Belgium.

Contact :  Prof. Kevin Braeckmans (Kevin.Braeckmans@UGent.be) and Prof. Katrien Remaut (Katrien.Remaut@UGent.be)


                                                       Pulmonary siRNA Delivery for the Treatment of Asthma and other Diseases
                                                                           Prof. Olivia Merkel -LMU Munich - olivia.merkel@lmu.de


RNA interference offers the potential to selectively silence disease-related genes in defined cell subsets. Translation into the clinical routine is, however, still hampered by the lack of efficient carrier systems for therapeutic siRNA delivery to organs other than the liver and by endosomal entrapment, presenting a major hurdle. For the treatment of asthma, pulmonary delivery of siRNA is a promising approach, and we have developed dry powder formulations which can be obtained by spray drying nanoparticle suspensions.[1] For the specific treatment of asthma, we have chosen a therapeutic target in T cells, which are, however notoriously very difficult to transfect. In this regard, we developed an siRNA delivery system based on polyethylenimine (PEI) and the targeting ligand transferrin (Tf) to specifically deliver siRNA to activated T cells in the lung.[2] [3] Furthermore, we report on strategies to enhance the endosomal escape of siRNA, by the use of the membrane lytic peptide melittin (Mel) [4] [5]. Therapeutic efficacy and biocompatibility are currently further evaluated in precision cut lung slices and in our acute mouse model of asthma. In conclusion, a novel siRNA delivery system able to specifically deliver nucleic acids to T cells is introduced and holds promise for several therapeutic applications.
References:
1. Keil et al., Eur J Pharm Biopharm, 2019. 143: p. 61-9.
2. Xie et al., J Control Release, 2016. 229: p. 120-9.
3. Kandil et al., Methods Mol Biol, 2019. 1943: p. 323-31.
4. Feldmann et al., J Control Release, 2018. 276: p. 50-58.
5. Kandil et al., Adv Therapeutics, 2019. pii: 1900047.

Biography Olivia Merkel
Olivia Merkel received a PhD in Pharmaceutics from Philipps-Universität Marburg, Germany, in 2009 and has been a Professor of Drug Delivery in the Department of Pharmacy at LMU Munich in Germany since 2015. From 2011 until 2017 she was an Assistant Professor of Pharmaceutics and an Associate Faculty Member of Oncology at Wayne State University, Detroit, MI, USA. She received several awards, including the Prinzessin-Therese von Bayern Award, an ERC Starting Grant, the Galenus Foundation Technology Award, the Young Investigator Award from the College of Pharmacy at Wayne State, the Young Pharmaceutical Investigator Award granted by the European Federation for Pharmaceutical Science, an invitation to the Lindau Nobel Laureates Meeting, the Carl-Wilhelm-Scheele-Award by the German Pharmaceutical Society (DPhG) and the award for the best PhD thesis at Philipps-Universität Marburg. Prof. Merkel is the author of over 70 peer reviewed articles, 13 book chapters and the editor of two books. She served as NIH reviewer from 2014-2015, is a standing international member of the Swiss National Science Foundation review board, Editorial Board member for the Journal of Controlled Release, the European Journal of Pharmaceutics and Biopharmaceutics and Molecular Pharmaceutics, and an honorary member of the Académie des Alpilles. Currently her research focuses on targeted siRNA delivery in cancer and inflammatory diseases.

 


                                        From dancing proteins to running mitochondria: Elucidating the dynamics of life using fluorescence
                                                                                          Prof. Don Lamb - LMU Munich - d.lamb@lmu.de

Twenty-five years ago, the ability to detect Förster Resonance Energy Transfer (FRET) on a single molecule was demonstrated. This ability to measure the motion of individual molecules on the nanometer scale has opened a whole new realm for investigating the function of biological systems. As a first example, I will discuss investigations of the dynamics, or dancing, of enzymes in the cellulosome. The linker connecting the cohensin subunits allows the enzymes to dynamically rearrange, giving them the necessary flexibility to optimize the degradation of cellulose (Barth et al., 2018). To studying DNA double strand break repair, we have developed a DNA origami platform. By keeping the two ends of the DNA in close proximity, we can keep the local concentration of DNA high enough to investigate their interaction while the origami concentration is low enough to allow us to perform single molecule studies.
Next, I will discuss our investigations of viral assembly. Here, we used ex post facto approaches to follow the assembly of HIV. We identified different phases of the assembly processes and investigated at what stage HIV interacts with the cellular proteins needed for escape (Baumgärtel et al., 2011; Ivanchenko et al., 2009). To investigate the first steps in HIV assembly within the cytosol, we resorted to Fluorescence Fluctuation Spectroscopy. Our results reveal potential nucleation steps of cytosolic Gag fractions prior to membrane-assisted Gag assembly (Hendrix et al., 2015).
In the last portion of this talk, I will talk about our orbital tracking feedback approach (Dupont and Lamb, 2011; Katayama et al., 2009). Using orbital tracking, we could follow single mitochondria transport in living zebra fish embryos over distances > 100 µm. Using this instrument, we could detect transport processes that were not observable previously as well as visualize roadblocks in the transport process (Wehnekamp et al., 2019).
Barth, A., Hendrix, J., Fried, D., Barak, Y., Bayer, E.A., and Lamb, D.C. (2018). Dynamic interactions of type I cohesin modules fine-tune the structure of the cellulosome of Clostridium thermocellum. Proc Natl Acad Sci U S A 115, E11274-E11283.
Baumgärtel, V., Ivanchenko, S., Dupont, A., Sergeev, M., Wiseman, P.W., Kräusslich, H.-G., Bräuchle, C., Müller, B., and Lamb, D.C. (2011). Live-cell Visualization of Dynamics of HIV Budding Site Interactions with an ESCRT Component. Nature Cell Biology 13, 469-474.
Dupont, A., and Lamb, D.C. (2011). Nanoscale three-dimensional single particle tracking. Nanoscale 3, 4532-4541.
Hendrix, J., Baumgartel, V., Schrimpf, W., Ivanchenko, S., Digman, M.A., Gratton, E., Krausslich, H.G., Muller, B., and Lamb, D.C. (2015). Live-cell observation of cytosolic HIV-1 assembly onset reveals RNA-interacting Gag oligomers. J Cell Biol 210, 629-646.
Ivanchenko, S., Godinez, W.J., Lampe, M., Kräusslich, H.-G., Eils, R., Rohr, K., Bräuchle, C., Müller, B., and Lamb, D.C. (2009). Dynamics of HIV-1 assembly and release. PLoS Pathogens 5, e1000652.
Katayama, Y., Burkacky, O., Meyer, M., Brauchle, C., Gratton, E., and Lamb, D.C. (2009). Real-time nanomicroscopy via three-dimensional single-particle tracking. Chemphyschem 10, 2458-2464.
Wehnekamp, F., Plucinska, G., Thong, R., Misgeld, T., and Lamb, D.C. (2019). Nanoresolution real-time 3D orbital tracking for studying mitochondrial trafficking in vertebrate axons in vivo. eLife 8.

Biography Don Lamb
Prof. Don Lamb received a PhD in Physics from the University of Illinois at Urbana-Champaign in 1993. He has been Group Leader and Professor at the Ludwig-Maximilian-University Munich since 2003. He received several awards and fellowships such as the Watkins Visiting Professorship (Wichita State University), the Romer Prize (LMU Munchen), the Alexander von Humboldt Research Fellowship, the Anderson Physics Scholarship (Illinois Wesleyan University) and the Alumni Scholarship (Illinois Wesleyan University). Prof. Lamb is the author of over 100 peer reviewed articles and 6 book chapters. He was organizer of several editions of the International Physics of Living Systems Meeting (iPoLS) in Munich and the European Workshop on Advanced Fluorescence Imaging and Dynamics, Munich and serves as reviewer for various federal funding agencies (Austria, France, Great Britain, Germany, Italy, Switzerland and USA) and for several journals including the Nature Journals, Science, PLoS, Angewandte Chemie, Biophysical Journal, Small, Journal of Physical Chemistry, ChemPhysChem, … His research interests are Ultra-sensitive fluorescence methods, Advanced Microscopy Methods, Single Molecule Studies, Protein function and dynamics, Chaperon Assisted Protein Folding, Fluorescence Fluctuation Spectroscopies, Live-Cell Imaging, Single Particle Tracking, Single Virus Tracing and DNA Nanodevices.