Investigation of exon skipping therapy in kidney organoids from Alport syndrome patients derived iPSCs

Abstract

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.