Molecular Medicine //
Science

Research goals

We will develop new gene and recombinant protein-based approaches for the treatment of cardiovascular diseases. Also, development of better gene transfer vectors and identification of new treatment genes for cardiovascular and ischemic diseases is the major focus of our research. Special emphasis is given to translational research applications and clinical trials based on our own discoveries.

Research Methods

Gene transfer technology with adenoviruses, lentiviruses, adenoassociated viruses and nanoparticles. Gene arrays, deep sequencing methods, general molecular biology techniques, cell culture, immunocytochemistry, general biochemistry methods, confocal and multiphoton microscopy, MRI and experimental animal work in rodents and large animals, clinical trials.

Latest achievements

We have shown vasculoprotective effect of VEGF gene therapy, characterized angiogenic and lymphangiogenic effects of the new members of the VEGF family (VEGF-B, VEGF-C, VEGF-D, VEGF-E, PLGF and their receptors) and identified several new candidate genes for the treatment of vascular diseases using DNA array and deep sequencing techniques. In phase I/II clinical gene therapy studies we have shown that VEGF-D gene transfer by adenovirus vectors can improve vascularity and perfusion in ischemic myocardium. In previous phase II and III studies we have shown that adenovirus thymidine kinase gene therapy can significantly improve the life expectancy of malignant glioma patients. In addition, several significant improvements have been made in gene therapy vectors, such as targeted integration of lentivirus vectors, and the first demonstration that promoter-targeted siRNAs can upregulate target gene expression via epigenetic mechanisms. This new approach has been named "Epigenetherapy".

Collaboration

Finland: Prof. Kari Alitalo, Prof. Heikki Ruskoaho, Dr. Karl Lemström, Prof. Arto Urtti (University of Helsinki); Prof. Markku Laakso, Prof. Juha Hartikainen, Prof. Hannu Manninen, Dr. Kimmo Mäkinen, Prof. Juha E Jääskeläinen, Prof. Kai Kaarniranta (University of Eastern Finland); Prof. Seppo Vainio (University of Oulu), Docents Maija Vihinen-Ranta, Varpu Marjomäki (University of Jyväskylä; Docent Juhana Frösen (Neurosurgery, Kuopio University Hospital)

European Union: Prof. John F. Martin, Prof. Ian Zachary and Prof. Anthony Mathur (University College London), Prof. Andrew Newby, (University of Bristol), Dr. Andrew Baker (University of Edinburgh), Prof. Johannes Waltenberger (University of Münster), Prof. Georg Breier (Max Planck Institute, Bad Nauheim), Prof. Ulf Eriksson (Karolinska Institute), Prof. Göran Hansson (Karolinska Institute), Dr. Arne Östman (University of Uppsala), Prof. Mat Daemen and Doc. Judith Sluimer (University of Maastricht), Prof. William Leenders (Radboud University, Nijmegen), Prof. Jozef Dulak (University of Krakow), Prof. Jörn Christensen (University of Copenhagen), Prof. Maria Gomez (University of Lund), Prof. Guido de Meyer (University of Antwerpen)

USA: Prof. Inder Verma (Salk Institute, San Diego), Prof. Theodore Friedmann (University of California, San Diego), Prof. Joseph Witztum (University of California, San Diego), Prof. Christopher Glass (University of California, San Diego), Prof. Karen Moulton (University of Colorado), Prof. Kevin Morris (Scripps Research Institute, San Diego)

Australia: Dr. Marc Achen (Ludwig Institute for Cancer Research, Melbourne), Dr. Steve Stacker (Ludwig Institute for Cancer Research, Melbourne)

Japan: Prof. Masabumi Shibuya (University of Tokyo)

Funding

University of Eastern Finland, Academy of Finland, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, European Union, Leducq Foundation and European Research Council Advanced Grant 2010-2015 and 2010-2020.

Our group was named as a Centre of Excellence for 2002- 2007, 2008-2013 and 2014-2019 by the Academy of Finland.

Selected publications

  1. E. Gurzeler, E. Aavik, A. Laine, T. Valkama, H. Niskanen, J. Huusko, M.U. Kaikkonen, S. Ylä-Herttuala, Therapeutic effects of rosuvastatin in hypercholesterolemic prediabetic mice in the absence of low density lipoprotein receptor, Biochim. Biophys. Acta - Gen. Subj., 1863 (2019) 481–490. https://doi.org/10.1016/j.bbagen.2018.11.012
  2. T. Nieminen, T. Scott, F.-M. Lin, Z. Chen, S. Yla-Herttuala, K. Morris, T. Nieminen, T.A. Scott, F.-M. Lin, Z. Chen, S. Yla-Herttuala, K. V. Morris, Long Non-Coding RNA Modulation of VEGF-A during Hypoxia, Non-Coding RNA, 4 (2018) 34. https://doi.org/10.3390/ncrna4040034
  3. T. Vuorio, E. Ylä-Herttuala, J.P. Laakkonen, S. Laidinen, T. Liimatainen, S. Ylä-Herttuala, Downregulation of VEGFR3 signaling alters cardiac lymphatic vessel organization and leads to a higher mortality after acute myocardial infarction, Sci. Rep., 8 (2018) 16709. https://doi.org/10.1038/s41598-018-34770-4
  4. A. Tirronen, T. Vuorio, S. Kettunen, K. Hokkanen, B. Ramms, H. Niskanen, H. Laakso, M.U. Kaikkonen, M. Jauhiainen, P.L.S.M. Gordts, S. Ylä-Herttuala, Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants, Arterioscler. Thromb. Vasc. Biol., 38 (2018) 2327–2337. https://doi.org/10.1161/ATVBAHA.118.311549
  5. E. Kokki, T. Karttunen, V. Olsson, K. Kinnunen, S. Ylä-Herttuala, E. Kokki, T. Karttunen, V. Olsson, K. Kinnunen, S. Ylä-Herttuala, Human Vascular Endothelial Growth Factor A165 Expression Induces the Mouse Model of Neovascular Age-Related Macular Degeneration, Genes (Basel)., 9 (2018) 438. https://doi.org/10.3390/genes9090438
  6. J.P. Hytönen, J. Taavitsainen, J.T.T. Laitinen, A. Partanen, K. Alitalo, O. Leppänen, S. Ylä-Herttuala, Local adventitial anti-angiogenic gene therapy reduces growth of vasa-vasorum and in-stent restenosis in WHHL rabbits, J. Mol. Cell. Cardiol., 121 (2018) 145–154. https://doi.org/10.1016/j.yjmcc.2018.07.007
  7. X. Que, M.-Y. Hung, C. Yeang, A. Gonen, T.A. Prohaska, X. Sun, C. Diehl, A. Määttä, D.E. Gaddis, K. Bowden, J. Pattison, J.G. MacDonald, S. Ylä-Herttuala, P.L. Mellon, C.C. Hedrick, K. Ley, Y.I. Miller, C.K. Glass, K.L. Peterson, C.J. Binder, et al., Oxidized phospholipids are proinflammatory and proatherogenic in hypercholesterolaemic mice, Nature, 558 (2018) 301–306. https://doi.org/10.1038/s41586-018-0198-8
  8. N.L. Downes, N. Laham-Karam, M.U. Kaikkonen, S. Ylä-Herttuala, Differential but Complementary HIF1α and HIF2α Transcriptional Regulation, Mol. Ther., 26 (2018) 1735–1745. https://doi.org/10.1016/j.ymthe.2018.05.004
  9. H. Belt, J.K. Koponen, T. Kekarainen, K.A. Puttonen, P.I. Mäkinen, H. Niskanen, J. Oja, G. Wirth, J. Koistinaho, M.U. Kaikkonen, S. Ylä-Herttuala, Temporal Dynamics of Gene Expression During Endothelial Cell Differentiation From Human iPS Cells: A Comparison Study of Signalling Factors and Small Molecules, Front. Cardiovasc. Med., 5 (2018) 16. https://doi.org/10.3389/fcvm.2018.00016
  10.  S.I. Nikolaev, S. Vetiska, X. Bonilla, E. Boudreau, S. Jauhiainen, B. Rezai Jahromi, N. Khyzha, P. V. DiStefano, S. Suutarinen, T.-R. Kiehl, V. Mendes Pereira, A.M. Herman, T. Krings, H. Andrade-Barazarte, T. Tung, T. Valiante, G. Zadeh, M. Tymianski, T. Rauramaa, S. Ylä-Herttuala, et al., Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain, N. Engl. J. Med., 378 (2018) 250–261. https://doi.org/10.1056/NEJMoa1709449