Institute of Molecular and Translational Therapeutic Strategies (IMTTS), Hannover Medical School, Hannover, Germany.
Center for Translational Regenerative Medicine, Hannover Medical School, Hannover, Germany.
J Transl Med. 2024 Oct 24;22(1):965. doi: 10.1186/s12967-024-05756-w.
Fabry disease is a multi-organ disease, caused by mutations in the GLA gene and leading to a progressive accumulation of glycosphingolipids due to enzymatic absence or malfunction of the encoded alpha-galactosidase A. Since pathomechanisms are not yet fully understood and available treatments are not efficient for all mutation types and tissues, further research is highly needed. This research involves many different model types, with significant effort towards the establishment of an in vivo model. However, these models did not replicate the variety of symptoms observed in patients. As an alternative strategy, patient-derived somatic cells as well as patient-independent cell lines were used to model specific aspects of the disease in vitro. Fabry disease patients present different phenotypes according to the mutation and the level of residual enzyme activity, pointing to the necessity of personalized disease modeling. With the advent of induced pluripotent stem cells, the derivation of a multitude of disease-affected cell types became possible, even in a patient-specific and mutation-specific manner. Only recently, three-dimensional Fabry disease models were established that even more closely resemble the native tissue of investigated organs and will bring research closer to the in vivo situation. This review provides an overview of human in vitro models and their achievements in unravelling the Fabry disease pathomechanism as well as in elucidating current and future treatment strategies.
法布瑞氏病是一种多器官疾病，由 GLA 基因突变引起，导致编码的α-半乳糖苷酶 A 缺乏或功能异常，使糖脂类物质渐进性累积。由于发病机制尚未完全阐明，且现有治疗方法对所有突变类型和组织均不有效，因此非常需要进一步的研究。该研究涉及许多不同的模型类型，其中建立体内模型的努力尤为显著。然而，这些模型无法复制患者中观察到的各种症状。因此，作为一种替代策略，使用患者来源的体细胞核移植细胞以及与患者无关的细胞系，在体外模拟疾病的特定方面。根据突变和残留酶活性水平，法布瑞氏病患者表现出不同的表型，这表明需要进行个性化疾病建模。随着诱导多能干细胞的出现，即使以患者特异性和突变特异性的方式，也可以衍生出多种疾病相关的细胞类型。直到最近，才建立了三维法布瑞氏病模型，这些模型更接近所研究器官的天然组织，使研究更接近体内情况。本综述概述了人类体外模型及其在揭示法布瑞氏病发病机制以及阐明当前和未来治疗策略方面的成就。
