Lymfactin

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Lymfactin is a biological medicine that was developed for the treatment of lymphedema . It is a viral vector for gene therapy with VEGF-C ; H. a VEGF-C gene is introduced into body cells with the help of recombinant adenoviruses . It is currently (as of 2019) being tested in phase II clinical trials in Finland and Sweden under the auspices of Herantis Pharma . The target group of the clinical studies are patients with secondary lymphedema after breast cancer surgery . The success rate of the existing lymph node transplantation treatment should be improved through the use of Lymfactin.

Mechanism of action

VEGF-C is the main growth factor that mediates lymphangiogenic signals. It is necessary to build lymphatic vessels and also to maintain some existing lymphatic vessels (e.g. in the intestines). Lymphedema can be caused by decreased lymphangiogenic signal transduction; H. the growth factor VEGF-C does not activate the VEGF receptor-3 to a sufficient degree (e.g. in hereditary lymphedema type I). The decreased signal transduction can be caused by:

  • Mutations in the VEGF-C gene (more rarely, hereditary lymphedema type ID)
  • Mutations in the VEGFR-3 gene (most common cause, hereditary lymphedema type IA)
  • Mutations in the ADAMTS3 gene (rare cause, Hennekam syndrome type III)
  • Mutations in the CCBE gene (rare cause, Hennekam syndrome type I)

Hereditary lymphedema type I is a dominant hereditary disease (i.e. only one of two alleles of the VEGFR-3 gene has been inactivated by mutation ). Since there are still enough functional VEGFR-3 molecules in these patients (25% of all receptors are still fully functional), the gene defect can be compensated for by increased activity of the non-mutated receptors, and the increased activity is achieved through increased stimulation by VEGF -C achieved. Studies led by Kari Alitalo have shown that a large amount of VEGF-C in mice can successfully treat the equivalent hereditary disease to human hereditary lymphedema type I ( Chy mouse ).

Individual evidence

  1. ↑ B. Enholm, T. Karpanen, M. Jeltsch, H. Kubo, F. Stenback, R. Prevo, DG Jackson, S. Yla-Herttuala, K. Alitalo: Adenoviral Expression of Vascular Endothelial Growth Factor-C Induces Lymphangiogenesis in the skin . In: Circulation Research . 88, No. 6, March 30, 2001, ISSN  0009-7330 , pp. 623-629. doi : 10.1161 / 01.RES.88.6.623 .
  2. ↑ Herantis Pharma Plc: Herantis Pharma announces initiation of Phase 2 study for Lymfactin® gene therapy in secondary lymphedema . In: Herantis Pharma . 2018. Retrieved October 4, 2018.
  3. ↑ Markku Lähteenvuo, Krista Honkonen, Tomi Tervala, Tuomas Tammela, Erkki Suominen, Johanna Lähteenvuo, Ivana Kholová, Kari Alitalo, Seppo Ylä-Herttuala, Anne Saaristo: Growth Factor Therapy and Autologous Lymph Node Transfer in LymphedemaClinical Perspective . In: Circulation . 123, No. 6, February 15, 2011, ISSN  0009-7322 , pp. 613-620. doi : 10.1161 / CIRCULATIONAHA.110.965384 . Retrieved February 23, 2012.
  4. ↑ Emilia Balboa-Beltran, María J. Fernández-Seara, Alejandro Pérez-Muñuzuri, Ramón Lago, Carlos García-Magán, María L. Couce, Beatriz Sobrino, Jorge Amigo, Angel Carracedo, Francisco Barros: A novel stop mutation in the vascular endothelial growth factor-C gene (VEGFC) results in Milroy-like disease . In: Journal of Medical Genetics . 51, No. 7, July 1, 2014, ISSN  0022-2593 , pp. 475-478. doi : 10.1136 / jmedgenet-2013-102020 . PMID 24744435 . Retrieved May 22, 2018.
  5. ↑ Kristiana Gordon, Dörte Schulte, Glen Brice, Michael A. Simpson, M. Guy Roukens, Andreas van Impel, Fiona Connell, Kamini Kalidas, Steve Jeffery, Peter S. Mortimer, Sahar Mansour, Stefan Schulte-Merker, Pia Ostergaard: Mutation in Vascular Endothelial Growth Factor-C, a Ligand for Vascular Endothelial Growth Factor Receptor-3, Is Associated With Autosomal Dominant Milroy-Like Primary Lymphedema Novelty and Significance . In: Circulation Research . 112, No. 6, March 15, 2013, ISSN  0009-7330 , pp. 956-960. doi : 10.1161 / CIRCRESAHA.113.300350 . Retrieved April 3, 2013.
  6. ↑ A. Ghalamkarpour, S. Morlot, A. Raas ‐ Rothschild, A. Utkus, JB Mulliken, LM Boon, M. Vikkula: Hereditary lymphedema type I associated with VEGFR3 mutation: the first de novo case and atypical presentations . In: Clinical Genetics . 70, No. 4, October 1, 2006, ISSN  1399-0004 , pp. 330-335. doi : 10.1111 / j.1399-0004.2006.00687.x .
  7. ↑ Alexandre Irrthum, Marika J. Karkkainen, Koen Devriendt, Kari Alitalo, Miikka Vikkula: Congenital Hereditary Lymphedema Caused by a Mutation That Inactivates VEGFR3 Tyrosine Kinase . In: The American Journal of Human Genetics . 67, No. 2, August 2000, ISSN  0002-9297 , pp. 295-301. doi : 10.1086 / 303019 .
  8. ↑ Pascal Brouillard, Laura Dupont, Raphael Helaers, Richard Coulie, George E. Tiller, Joseph Peeden, Alain Colige, Miikka Vikkula: Loss of ADAMTS3 activity causes Hennekam lymphangiectasia – lymphedema syndrome 3 . In: Human Molecular Genetics . 26, No. 21, November 1, 2017, ISSN  0964-6906 , pp. 4095-4104. doi : 10.1093 / hmg / ddx297 . Retrieved May 22, 2018.
  9. ↑ Sawan Kumar Jha, Khushbu Rauniyar, Terhi Karpanen, Veli-Matti Leppänen, Pascal Brouillard, Miikka Vikkula, Kari Alitalo, Michael Jeltsch: Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1 . In: Scientific Reports . 7, No. 1, July 7, 2017, ISSN  2045-2322 , p. 4916. doi : 10.1038 / s41598-017-04982-1 .
  10. ↑ Marielle Alders, Benjamin M Hogan, Evisa Gjini, Faranak Salehi, Lihadh Al-Gazali, Eric A Hennekam, Eva E Holmberg, Marcel MAM Mannens, Margot F Mulder, G Johan A Offerhaus, Trine E Prescott, Eelco J Schroor, Joke BGM Verheij, Merlijn Witte, Petra J Zwijnenburg, Mikka Vikkula, Stefan Schulte-Merker, Raoul C Hennekam: Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans . In: Nature Genetics . 41, No. 12, 2009, ISSN  1061-4036 , pp. 1272-1274. doi : 10.1038 / ng.484 .
  11. ↑ Michael Jeltsch, Sawan Kumar Jha, Denis Tvorogov, Andrey Anisimov, Veli-Matti Leppänen, Tanja Holopainen, Riikka Kivelä, Sagrario Ortega, Terhi Kärpanen, Kari Alitalo: CCBE1 Enhances Lymphangiogenesis via A Disintegrin and Metalloprotease Vascular-3-Mediated Motifs Endothelial Growth Factor-C Activation . In: Circulation . 129, No. 19, May 13, 2014, ISSN  0009-7322 , pp. 1962–1971. doi : 10.1161 / CIRCULATIONAHA.113.002779 . PMID 24552833 .
  12. ↑ Marika J. Karkkainen, Anne Saaristo, Lotta Jussila, Kaisa A. Karila, Elizabeth C. Lawrence, Katri Pajusola, Hansruedi Bueler, Anne Eichmann, Risto Kauppinen, Mikko I. Kettunen, Seppo Ylä-Herttuala, David N. Finegold, Robert E. Ferrell, Kari Alitalo: A model for gene therapy of human hereditary lymphedema . In: Proceedings of the National Academy of Sciences . 98, No. 22, October 23, 2001, ISSN  0027-8424 , pp. 12677-12682. doi : 10.1073 / pnas.221449198 .