Pathophysiology of aniridia-associated keratopathy: developmental aspects and unanswered questions

© 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Aniridia, a rare congenital disease, is often characterized by a progressive, pronounced limbal insufficiency and ocular surface pathology termed aniridia-associated keratopathy (AAK). Due to the characteristics of AAK and its bilateral nature, clinical management is challenging and complicated by the multiple coexisting ocular and systemic morbidities in aniridia. Although it is primarily assumed that AAK originates from a congenital limbal stem cell deficiency, in recent years AAK and its pathogenesis has been questioned in the light of new evidence and a refined understanding of ocular development and the biology of limbal stem cells (LSCs) and their niche. Here, by consolidating and comparing the latest clinical and preclinical evidence, we discuss key unanswered questions regarding ocular developmental aspects crucial to AAK. We also highlight hypotheses on the potential role of LSCs and the ocular surface microenvironment in AAK. The insights thus gained lead to a greater appreciation for the role of developmental and cellular processes in the emergence of AAK. They also highlight areas for future research to enable a deeper understanding of aniridia, and thereby the potential to develop new treatments for this rare but blinding ocular surface disease.This review is based upon work from the Work Group5 of the COST Action CA18116 (Aniridia: networking to address an unmet medical, scientific, and societal challenge), supported by COST (European Cooperation in Science and Technology). The European Joint Programme on Rare Diseases (EJP RD 2020) is acknowledged for its support to NL, LL, DA, MJC, NS, RAP (AAK-INSIGHT). The work of LL and NS at the Dr. Rolf M. Schwiete Center for Limbal Stem Cell and Congenital Aniridia Research at Saarland University, Germany was supported by the Dr. Rolf M. Schwiete Foundation.