阿尔波特综合征 (AS) 是一种由 COL4A5 基因突变引起的遗传性疾病，可导致慢性肾脏疾病。目前，尚未开发出具体的治疗方法。然而，最近一项使用 AS 模型小鼠的研究表明，外显子跳跃方法可以部分缓解症状。在这项研究中，我们使用 AS 患者衍生的诱导多能干细胞 (AS-iPSC) 生成的肾脏类器官评估了外显子跳跃法的效果。我们从 AS-iPSC 中生成了具有肾单位结构的肾脏类器官。正如预期的那样，COL4A5 的 C 末端在 AS 类器官中不表达。有趣的是，反义寡核苷酸在体外恢复了 COL4A5 C 末端的表达。接下来，我们将 AS 类器官移植到小鼠体内并评估体内肾小球基底膜的形成。我们发现与对照类器官相比，AS 类器官形成了较低的狭缝隔膜比。最后，我们评估了外显子跳跃对移植类器官的影响，但观察到了最小的影响。这些研究表明 AS-iPSC 可以生成缺乏 COL4A5 C 末端的肾脏类器官，并且外显子跳跃可以诱导其体外表达。© 2024 作者。日本分子生物学会和约翰·威利出版的《基因到细胞》

Alport syndrome (AS) is a hereditary disease caused by mutations in the COL4A5 gene and leads to chronic kidney disease. Currently, no specific treatment has been developed. However, a recent study using AS-model mice demonstrated that the exon skipping method could partially rescue the symptoms. In this study, we evaluated the effects of the exon skipping method using kidney organoids generated from AS-patient-derived induced pluripotent stem cells (AS-iPSCs). We generated kidney organoids from AS-iPSCs, which exhibited nephron structures. As expected, the C-terminus of COL4A5 was not expressed in AS-organoids. Interestingly, anti-sense oligonucleotides restored the expression of the C-terminus of COL4A5 in vitro. Next, we transplanted AS-organoids into mice and evaluated glomerular basement membrane formation in vivo. We found that AS-organoids formed a lower slit diaphragm ratio compared to control organoids. Finally, we assessed the effects of exon skipping on transplanted organoids but observed minimum effects. These studies suggest that AS-iPSCs can generate kidney organoids lacking the C-terminus of COL4A5, and that exon skipping can induce its expression in vitro.© 2024 The Author(s). Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.