Project: A03

Personalized anti(lymph)angiogenic and immune modulatory therapies in high-risk corneal transplantation

The healthy cornea is the avascular and transparent “windscreen” of the eye. Several pathologic insults such as chemical or thermal burns, infections, autoimmune diseases, transplant rejection, contact lens-induced hypoxia and trauma can lead to corneal blindness secondary to pathologic corneal neovascularisation and scarring. In addition, these conditions also lead to a so-called “high-risk situation” with increased rejection rates after subsequent corneal transplantation, which is the main cure for corneal blindness. We have previously identified clinically invisible corneal lymphatic vessels as key players defining a high-risk setting. We then showed that targeting pathologic corneal (lymph)angiogenesis in the murine model of corneal high-risk transplantation significantly promotes corneal graft survival. This was achieved either pharmacologically e.g. via VEGF A/C/D depletion or by mechanical lymphangioregression (using, e.g. fine needle cautery). Initial pilot data suggest that this concept of lymphangioregressive pretreatment improves high-risk graft survival also in patients. In fact, a pilot randomised clinical trial is starting in 2022 testing UVA crosslinking to regress lymphatic vessels and promote graft survival in high-risk recipients (BMBF; KS2020-188).However, pilot data from our group also suggest that all the abovementioned different corneal insults leading to a high-risk setting cause different immunological and (lymph)vascular tissue alterations in the recipient. Nonetheless, irrespective of the underlying cause, corticosteroids have hitherto remained the mainstay of immunomodulatory therapy after high-risk corneal transplantation. Similarly, there is no personalised or disease-specific antilymphangiogenic or -regressive approach available as yet for different underlying diseases. Personalised medicine, already approaching clinical routine in oncology, has not reached corneal transplantation medicine yet. Therefore, the aim of this project is to develop personalised and disease-specific immunomodulatory and lymphangiomodulatory therapies pre and post high-risk corneal transplantation due to different underlying diseases to promote graft survival and vision.

Key methods: in vivo models of corneal diseases, RNASeq, Proteomics, bioinformatics, cytokine bead arrays, cell culture, flow cytometry, next generation image analysis, IF