Research Collection. Novel Treatment of Chronic Skin Inflammation by Targeted Delivery of VEGF-C and Activation of the Lymphatic Vasculature
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1 Research Collection Doctoral Thesis Novel Treatment of Chronic Skin Inflammation by Targeted Delivery of VEGF-C and Activation of the Lymphatic Vasculature Author(s): Schwager, Simon Publication Date: 2018 Permanent Link: This page was generated automatically upon download from the ETH Zurich Research Collection. For more information please consult the Terms of use. ETH Library
2 DISS. ETH NO Novel treatment of chronic skin inflammation by targeted delivery of VEGF-C and activation of the lymphatic vasculature A thesis submitted to attain the degree of Doctor of Sciences of ETH Zurich (Dr. sc. ETH Zurich) presented by Simon Christoph Schwager MSc. Pharmaceutical Sciences ETH Zurich, Switzerland born on August 25, 1988 citizen of Bichelsee-Balterswil, Thurgau, Switzerland accepted on the recommendation of Prof. Dr. Michael Detmar, examiner Prof. Dr. Dario Neri, co-examiner 2018
3 1 1.1 Summary Chronic inflammatory diseases like rheumatoid arthritis, chronic inflammatory bowel disease and psoriasis affect a large proportion of the population and represent a major and often life- long burden for the patients, as they negatively impact quality of life, are associated with comorbidities and necessitate costly therapy and care. While a wide range of therapeutic agents for the treatment of chronic inflammation is clinically available, they are not always effective and may be associated with severe side effects. Consequently, there is a need to develop new therapies for the treatment of chronic inflammatory diseases. In the main project of this thesis, we aimed to develop a therapeutic protein for the targeted activation of the lymphatic vasculature at the site of inflammation, as induction of lymphatic vessels has been shown to be beneficial in a variety of inflammatory disease models. To this end, we designed a fusion protein consisting of the lymphangiogenic vascular endothelial growth factor C (VEGF- C) linked to the F8 diabody specific to the alternatively- spliced, angiogenesis- marking extradomain A (EDA) of fibronectin, which is expressed in inflamed tissue. F8- VEGF- C was tested in two mouse models of chronic, psoriasis- like skin inflammation; either mediated by transgenic vascular endothelial growth factor A (VEGF- A) overexpression or by repeated application of imiquimod. After intravenous injection, F8- VEGF- C accumulated in the inflamed ear skin and significantly reduced ear edema compared to an untargeted VEGF- C construct. Histological analysis revealed a marked expansion of the lymphatic vasculature in the inflamed ears. Clearance assays employing an exclusively lymphatic- drained near- infrared dye demonstrated that administration of the fusion protein enhanced lymphatic clearance, thus indicating that the newly formed vessels were indeed functional. In addition, flow cytometric analysis of inflamed ears showed a significant reduction of overall leukocytes, which is at least partially caused by reduced numbers of regulatory T cells and γδ T cells after treatment with F8- VEGF- C. 1
4 In a second project, we investigated the effects of targeted VEGF- C delivery on tissue regeneration. Using a mouse model of full- thickness excisional wound healing, histological analysis demonstrated EDA expression in the injured skin seven days after wounding as well as prominent expansion of the blood vasculature in the granulation tissue upon administration of F8- VEGF- C compared to PBS. Moreover, lymphatic vessels in the skin adjacent to the wound site had expanded and displayed an enlarged morphology after treatment with the fusion protein, while the wound closure was not affected. Analysis of the injured skin 14 days after wounding revealed no striking changes in the blood and lymphatic vasculature or collagen deposition between PBS- and F8- VEGF- C- treated animals, suggesting that the vascular changes observed in seven- day wounds were transient, at least in acute wound healing in non- diabetic mice. Collectively, our results demonstrate that inflammation site- specific induction of the lymphatic vasculature by targeted delivery of VEGF- C represents a new, innovative and promising approach for the treatment of chronic inflammatory diseases and may also be applicable for the therapy of chronic wounds. 2
5 1.2 Zusammenfassung Chronisch- entzündliche Erkrankungen, beispielsweise rheumatoide Arthritis, chronisch- entzündliche Darmerkrankungen und Psoriasis, betreffen einen wachsenden Anteil der Bevölkerung und stellen eine grosse Belastung für die Patienten dar, da diese Krankheiten die Lebensqualität stark beeinträchtigen, mit zeit- und kostenintensiven Behandlungen einhergehen und darüber hinaus häufig mit schweren Begleiterkrankungen verbunden sind. Aufgrund mangelhafter Verträglichkeit oder fehlender Wirksamkeit können trotz einer Vielzahl an zugelassenen Therapien nicht alle Patienten zufriedenstellend behandelt werden. Daher besteht ein anhaltender Bedarf an der Entwicklung neuer therapeutischer Ansätze für die Behandlung chronisch- entzündlicher Erkrankungen. Der Schwerpunkt dieses Projekts lag auf der Entwicklung eines therapeutischen Proteins, welches die lymphatischen Gefässe gezielt am Ort der Entzündung stimuliert. Dies ist erstrebenswert, da die Aktivierung der lymphatischen Gefässe in mehreren Krankheitsmodellen mit einer Linderung der Entzündung in Verbindung gebracht werden konnte. Zu diesem Zweck entwarfen wir ein Fusionsprotein, welches aus dem lymphangiogenen Vascular Endothelial Growth Factor C (VEGF- C) und dem F8- Diabody besteht. Durch die Spezifität des F8- Diabodys für die alternativ gespleisste Extradomäne A (EDA) von Fibronectin, deren Expression im erwachsenen Organismus fast ausschliesslich auf entzündetes Gewebe begrenzt ist, wird die gezielte Zuführung des VEGF- C gewährleistet. Das resultierende Fusionsprotein F8- VEGF- C wurde in zwei Mausmodellen von chronischer, psoriasisähnlicher Hautentzündung getestet, welche entweder durch die transgene Überexpression von Vascular Endothelial Growth Factor A (VEGF- A) oder durch wiederholtes Auftragen einer imiquimodhaltigen Crème ausgelöst wurde. Intravenös injiziertes F8- VEGF- C reicherte sich in den entzündeten Ohren an und reduzierte die ödemartige Hautschwellung im Vergleich zu einem nichtzielgerichteten VEGF- C Fusionsprotein signifikant. In histologischen Untersuchungen zeigte sich eine starke Expansion des lymphatischen Gefässsystems in den entzündeten Ohren. 3
6 In Experimenten mit einem lymphatisch- spezifischen Tracer im Nahinfrarotbereich stellte sich zudem heraus, dass die Behandlung mit F8- VEGF- C die lymphatische Drainagefunktion deutlich verbesserte, was darauf hinweist, dass die neugebildeten lymphatischen Gefässe funktionstüchtig waren. Durchflusszytometrische Analysen ergaben zudem, dass Injektionen von F8- VEGF- C zu einer signifikanten Verringerung von Leukozyten führten, welche zumindest teilweise in einer Reduktion von regulatorischen T- Zellen und γδ T- Zellen begründet liegt. In einem zweiten Projekt untersuchten wir die Auswirkungen von wiederholten Injektionen zielgerichteten VEGF- Cs auf die Wundheilung. In einem Mausmodell tiefer Wunden war EDA sieben Tage nach der Verletzung in der betroffenen Haut exprimiert und die Behandlung mit F8- VEGF- C führte zu einer markanten Expansion der Blutgefässe im Granulationsgewebe. Die lymphatischen Gefässe in der die Wunde umgebenden Haut waren ebenfalls expandiert und vergrössert, die Wundheilung wurde durch F8- VEGF- C jedoch nicht beeinflusst. Zu einem späteren Zeitpunkt, 14 Tage nach der Wundsetzung, zeigten die Blut- und Lymphgefässe keinen auffälligen Phänotyp mehr und die Kollagenablagerung war vergleichbar in PBS- und F8- VEGF- C- behandelten Tieren. Dies impliziert, dass die Veränderungen, welche sich in den siebentägigen Wunden feststellen liessen, zumindest in nichtdiabetischen Mäusen vorübergehender Natur waren. Zusammengefasst weisen unsere Resultate darauf hin, dass die spezifische Aktivierung der lymphatischen Gefässe im entzündeten Gewebe durch die Verabreichung zielgerichteten VEGF- Cs einen neuen, innovativen und vielversprechenden Behandlungsansatz für chronisch- entzündliche Erkrankungen darstellt, welcher auch in der Therapie von chronischen Wunden zur Anwendung kommen könnte. 4
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