Miller Jason M L, Thompson Benjamin R, Handa James T, Luthert Philip, Chakravarthy Usha, Csaky Karl G, Bird Alan, Young Benjamin K, Iyengar Sudha K, Baek Jiwon, Zouache Moussa A, Richards Burt T, Hageman Gregory S, Rodrigues Gerry, Bharti Kapil, Flannery John G, Gorin Michael B, Bowes Rickman Catherine
University of Michigan, Kellogg Eye Center and Cellular and Molecular Biology Program, Ann Arbor, MI, USA.
Northwestern University Feinberg School of Medicine, Department of Ophthalmology and Feinberg Cardiovascular and Renal Research Inst., Chicago, IL, USA.
Exp Eye Res. 2025 May;254:110304. doi: 10.1016/j.exer.2025.110304. Epub 2025 Feb 19.
Clinicians recognize the heterogeneity of age-related macular degeneration (AMD) in presentation, progression, and treatment response, as well as the challenges in distinguishing it from other macular degenerations. As part of the 2024 Ryan Initiative for Macular Research meeting, a group of clinician-scientists and basic scientists were convened to consider the question of whether AMD should be classified as a single disorder or a spectrum of conditions. To answer this question, we reviewed research on several "dimensions" that constitute AMD risk or pathogenesis: genetics, ancestry, retinal imaging findings, diet and environment, aging, and outer retinal molecular and cellular pathways. The group reached a consensus that AMD represents a heterogeneous collection of disease states arising from the interplay of these dimensions. This heterogeneity can be conceived of as a "cloud" of AMD phenotypes. Defining subtypes within this "cloud" requires longitudinal cohorts of well-genotyped and phenotyped patients who progress from no AMD through late AMD, analyzed by unsupervised learning. Comparing the AMD subtypes that emerge from this analysis, especially -omics data from each subtype, will illuminate biology that is applicable to certain subtypes of AMD patients and molecular pathogenic mechanisms that universally apply to all AMD. This knowledge will, in turn, drive improved drug development.
临床医生认识到年龄相关性黄斑变性(AMD)在表现、进展和治疗反应方面存在异质性,以及将其与其他黄斑变性区分开来所面临的挑战。作为2024年瑞安黄斑研究倡议会议的一部分,召集了一组临床医生科学家和基础科学家,以探讨AMD应被归类为单一疾病还是一系列病症的问题。为了回答这个问题,我们回顾了关于构成AMD风险或发病机制的几个“维度”的研究:遗传学、血统、视网膜成像结果、饮食和环境、衰老以及视网膜外层分子和细胞途径。该小组达成共识,认为AMD代表了由这些维度相互作用产生的多种异质性疾病状态。这种异质性可以被设想为AMD表型的“云”。在这个“云”中定义亚型需要对从无AMD进展到晚期AMD的基因分型和表型良好的患者进行纵向队列研究,并通过无监督学习进行分析。比较从该分析中出现的AMD亚型,特别是每个亚型的组学数据,将阐明适用于某些AMD患者亚型的生物学特性以及普遍适用于所有AMD的分子致病机制。反过来,这些知识将推动药物研发的改进。