Research

Research goals

We will develop new gene and recombinant protein-based approaches for the treatment of cardiovascular diseases and malignant glioma. Also, development of better gene transfer vectors and identification of new treatment genes for cardiovascular diseases is the major focus of our research. 

Latest achievements

We have shown vasculoprotective effect of VEGF gene therapy, characterized angiogenic and lymphangiogenic effects of the members of the VEGF family (VEGF-A, 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 II clinical gene therapy studies we have shown that VEGFadenovirus can improve vascularity in leg muscles and improve perfusion in myocardium. Also, in a 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, including 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, Dr. Petri Koskinen, Dr. Karl Lemström, Prof. Arto Urtti (University of Helsinki); Prof. Markku Laakso, Prof. Matti Uusitupa, Prof. Leena Alhonen, Prof. Juha E Jääskeläinen, Prof. Seppo Heinonen, Prof. Carsten Carlberg, Prof. Kai Kaarniranta (University of Eastern Finland); Prof. Hans Söderlund (VTT), Prof. Markku Kulomaa (University of Tampere), Prof. Heikki Ruskoaho, Prof. Seppo Vainio (University of Oulu), Prof. Maija Vihinen-Ranta and doc. Varpu Marjomäki (University of Jyväskylä)

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 Glasgow), Prof. Johannes Waltenberger (University of Münster), Prof. Georg Breier (Max Planck Institute, Bad Nauheim), Dr. Peter Carmeliet (University of Leuven), Prof. Ulf Eriksson (Karolinska Institute, Sweden), Prof. Göran Hansson (Karolinska Institute, Sweden), Dr. Arne Östman (University of Uppsala), Prof. Mat Daemen and Doc. Judith Sluimer (University of Maastricht), Prof. William Leenders (Radboud University, Nijmegen, the Netherlands), Prof. Jozef Dulak (University of Krakow)

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)

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), Prof. Tatsuhiko Kodama (University of Tokyo)

Research Methods

Gene transfer technology with nonviral vectors and with adenoviruses, lentiviruses, adenoassociated viruses and baculoviruses. Gene arrays, laser capture microscopy, general molecular biology techniques, immunocytochemistry, cell culture, general biochemistry methods, MRI and experimental animal work.

Funding

University of Eastern Finland, Academy of Finland, Tekes, Sigrid Jusélius Foundation, Finnish Foundation for Cardiovascular Research, Ludwig Institute for Cancer Research,European Union, Leducq Foundation and European Research Council. 

The Molecular Medicine group was named as a Centre of Excellence for 2002- 2007 and 2008-2013 by the Academy of Finland.

Selected Publications

• Ylä-Herttuala S, Martin JF. Cardiovascular gene therapy. Lancet  2000, 355:213-222.
• Laukkanen J, Lehtolainen P, Gough PJ, Graeves DR, Gordon S, Ylä-Herttuala S. Adenovirus-mediated gene transfer of a secreted form of human macrophage scavenger receptor inhibits modified low-density lipoprotein degradiation and foam-cell formation in macrophages. Circulation 2000, 101:1091-1096.
• Mäkinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S-I, Ylä-Herttuala S, Alitalo K. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 2001, 7(2):199-205.
• Laukkanen MO, Kivelä A, Rissanen T, Rutanen J, Karkkainen MK, Leppanen O, Bräsen JH, Yla-Herttuala S. Adenovirus-mediated extracellular superoxide dismutase gene therapy reduces neointima formation in balloon-denuded rabbit aorta. Circulation 2002, 106:1999-2003.
• Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI, Kholová I, Kauppinen RA, Achen MG, Stacker SA, Alitalo K, Ylä-Herttuala S. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res 2003, 92:1098-1106.
• Hedman M, Hartikainen J, Syvänne M, Stjernvall J, Hedman A, Kivelä A, Vanninen E, Mussalo H, Kauppila E, Simula S, Närvänen O, Rantala A, Peuhkurinen K, Nieminen MS, Laakso M, Ylä-Herttuala S. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003,107:2677-2683.
• Ylä-Herttuala S, Alitalo K. Gene transfer as a tool to induce therapeutic vascular growth. Nat Med 2003. 9:694-701.
• Rutanen J, Rissanen TT, Markkanen JE, Gruchala M, Silvennoinen P, Kivelä A., Hedman A., Hedman M, Heikura T, Orden M-R, Stacker SA., Achen MG, Hartikainen J, Ylä-Herttuala S. Adenoviral catheter- mediated intramyocardial gene transfer using the mature form of vascular endothelial growth factor-D induces transmural  angiogenesis in porcine heart. Circulation 2004, 109:1029-1035.
• Leppänen O, Rutanen J, Hiltunen MO, Rissanen TT, Turunen MP, Sjöblom T, Brüggen J, Backström G, Carlsson M, Buchdunger E, Bergqvist D, Alitalo K, Heldin C-H, Östman A, Ylä-Herttuala S. Oral imatinib mesylate (STI571/Gleevec) improves the efficacy of local intravascular vascular endothelial growth factor-C gene transfer in reducing neointimal growth in hypercholesterolemic rabbits. Circulation 2004,109:1140- 1146.
• Rissanen TT, Korpisalo P, Markkanen JE, Liimatainen T, Ordén MR, Kholová I, de Goede A, Heikura T, Gröhn OH, Ylä-Herttuala S.  Blood flow remodels growing vasculature during vascular endothelial growth factor gene therapy and determines between capillary arterialization and sprouting angiogenesis. Circulation 2005, 112:3937-3946.
• Korpisalo P, Karvinen H, Rissanen TT, Kilpijoki J, Marjomäki V, Baluk P, McDonald DM, Cao Y, Eriksson U, Alitalo K, Ylä-Herttuala S. Vascular endothelial growth factor-A and platelet-derived growth factor-B combination gene therapy prolongs angiogenic effects via recruitment of interstitial mononuclear cells and paracrine effects rather than improved pericyte coverage of angiogenic vessels. Circ Res 2008, 103:1092-1099.
• Viita H, Markkanen J, Eriksson E, Nurminen M, Kinnunen K, Babu M, Heikura T, Turpeinen S, Laidinen S, Takalo T, Ylä-Herttuala S. 15-lipoxygenase-1 prevents vascular endothelial growth factor A- and placental growth factor-induced angiogenic effects in rabbit skeletal muscles via reduction in growth factor mRNA levels, NO bioactivity, and downregulation of VEGF receptor 2 expression. Circ Res 2008, 102:177-184.
• Lähteenvuo JE, Lähteenvuo MT, Kivelä A, Rosenlew C, Falkevall A, Klar J, Heikura T, Rissanen TT, Vähäkangas E, Korpisalo P, Enholm B, Carmeliet P, Alitalo K, Eriksson U, Ylä-Herttuala S. Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1 and Neuropilin receptor-1 dependent mechanisms. Circulation 2009, 119:845-856.
• Turunen MP, Lehtola T, Heinonen SE, Assefa GS, Korpisalo P, Girnary R, Glass CK, Väisänen S, Ylä-Herttuala S. Efficient regulation of VEGF expression by promoter-targeted lentiviral shRNAs based on epigenetic mechanism: a novel example of epigenetherapy.  Circ Res 2009, 105:604-609. 
• Hagberg CE, Falkewall A, Wang X, Klar J, Larsson E, Huusko J, Nilsson I, van Meeteren LA, Samen  E, Lu L, Vanwildemeersch M, Klar J, Genove G, Pietras K, Stone-Elander S, Claesson-Welsh L, Ylä-Herttuala S, Lindahl P, Eriksson U. Vascular endothelial growth factor B controls endothelial fatty acid uptake. Nature 2010,  464: 917-921.
• Korpisalo, P., Hytönen, J.P., Laitinen, J., Laidinen, S., Parviainen, H., Karvinen, H., Siponen, J., Marjomäki, V., Vajanto, I., Rissanen, T.T., Ylä-Herttuala, S. Capillary enlargement, not sprouting angiogenesis, determines beneficial therapeutic effects and side-effects of angiogenic gene therapy. Eur Heart J. 32; 1664-1672, 2011.
• Ylä-Herttuala, S., Bentzon, J.F., Daemen, M., Falk, E., Garcia-Garcia, H.M., Herrmann, J., Hoefer, I., Jauhiainen, S., Jukema, J.W., Krams, R., Kwak, B.R., Marx, N., Naruszewicz, M., Newby, A., Pasterkamp, G., Serruys, P.W.J.C., Waltenberger, J., Weber, C., Tokgözoglu, L. Stabilisation of atherosclerotic plaques. Eur. Heart J. 2012, accepted for publication.