Update on CXL‐induced lymphangioregression to promote high‐risk corneal graft survival
Authors: Wiedemann Johanna , Hos Deniz , Cursiefen Claus 
Published: January 2025

Vision is one of the most important sensory functions of all. Good vision highly depends on the transparency of the cornea, the avascular "windshield" and the most important refractive element of the eye.Loss of corneal transparency is a major cause of blindness globally, with corneal transplantation being the primary treatment. The cornea is normally free of blood and lymphatic vessels, but severe inflammation can lead to corneal neovascularization, affecting the success of a transplantation. While transplants in non‐vascularized recipient beds have very good long‐term success rates, those in so‐called high‐risk recipients with pre‐existing vascularization are much lower. In fact, rejection rates in these vascularized high‐risk eyes reach more than 50 % and even HLA matching and systemic immunosuppression in addition to standard local immunomodulation have not been able to significantly improve this poor prognosis. Therefore, there is a high unmet need for further optimization of high‐risk keratoplasty.We and other groups were able to show in preliminary work that the extent of pathological corneal neovascularization, blood and lymphatic in the recipient before keratoplasty correlates strongly with the risk of subsequent graft rejection. Based on these findings, we and others have shown that targeting blood and lymphatic vessels in pathologically vascularized eyes prior to keratoplasty can significantly improve graft survival in mouse models. This novel concept of improving graft survival by preconditioning the recipient through (lymph)angioregressive pretreatment prior to keratoplasty was subsequently validated using various models and (lymph)angioregressive approaches (such as fine needle diathermy [FND], photodynamic therapy and CXL).Based on these preclinical findings, we and others have used such angioregressive therapeutic approaches in small pilot series in patients with prevascularized high‐risk eyes and could confirm the previous results from the preclinical studies.However, it should be noted that all mentioned studies so far were retrospective in nature without internal controls and with small sample sizes.Since december 2023 we started the CrossCornealVision Study at Cologne University Eye Hospital and six further sites (University of: Berlin, Duesseldorf, Freiburg, Homburg Saar, Munich, Rostock) an exploratory investigator‐initiated trial with the purpose to improve the survival of transplanted corneal grafts by treating pathologically vascularized recipient corneas with (lymph)angioregressive therapy using corneal crosslinking (CXL) before high‐risk transplantation. Prior to high‐risk transplantation, patients will be randomized to receive either CXL or no CXL (control). Subsequently, the incidence of graft rejection after keratoplasty will be evaluated and safety evaluated. The primary endpoint is the incidence of graft rejection episodes over 24 months, while secondary endpoints include overall graft survival and regression of corneal vessels.If successful, this novel approach of graft preconditionning by (lymph)angioregressive treatment would be the first to improve graft survival in high‐risk transplants in decades and would thus significantly improve the vision and quality of life of affected patients suffering from corneal blindness.