Javidjam Dina, Moustardas Petros, Abbasi Mojdeh, Dashti Ava, Rautavaara Yedizza, Lagali Neil
JCI Insight. 2024 Dec 3;10(2):e183965. doi: 10.1172/jci.insight.183965.
Aniridia is a rare congenital condition of abnormal eye development arising principally from heterozygous mutation of the PAX6 gene. Among the multiple complications arising in the eye, aniridia-associated keratopathy (AAK) is a severe vision-impairing condition of the cornea associated with a progressive limbal stem cell deficiency that lacks suitable treatment options. Current mouse models of aniridia do not accurately represent the onset and progression dynamics of human AAK, hindering therapy development. Here, we performed deep phenotyping of a haploinsufficient Pax6+/- small-eye (Sey) mouse model on the 129S1/SvImJ background, which exhibits key features of mild presentation at birth and progressive AAK with aging, mimicking human disease. The model exhibits a slowly progressing AAK phenotype and provides insights into the disease, including disturbed basal epithelial cell organization, function, and marker expression; persistent postnatal lymphangiogenesis; disrupted corneal innervation patterns; and persisting yet altered limbal stem cell marker expression with age. The model recapitulates many of the known features of human disease, enabling investigation of underlying disease mechanisms and, importantly, access to a well-defined temporal window for evaluating future therapeutics.
无虹膜症是一种罕见的先天性眼部发育异常疾病，主要由PAX6基因的杂合突变引起。在眼部出现的多种并发症中，无虹膜症相关角膜病变（AAK）是一种严重的角膜视力损害疾病，与渐进性角膜缘干细胞缺乏相关，目前缺乏合适的治疗方法。现有的无虹膜症小鼠模型不能准确反映人类AAK的发病和进展动态，阻碍了治疗方法的开发。在此，我们对129S1/SvImJ背景下的单倍体不足Pax6+/-小眼（Sey）小鼠模型进行了深度表型分析，该模型表现出出生时轻度表现以及随着年龄增长出现渐进性AAK的关键特征，类似于人类疾病。该模型呈现出缓慢进展的AAK表型，并为该疾病提供了深入见解，包括基底上皮细胞组织、功能和标志物表达紊乱；出生后持续性淋巴管生成；角膜神经支配模式紊乱；以及随着年龄增长角膜缘干细胞标志物表达持续但发生改变。该模型概括了人类疾病的许多已知特征，有助于研究潜在的疾病机制，重要的是，能够进入一个明确的时间窗口来评估未来的治疗方法。
