Podocyte specific exon skipping after disease onset improves kidney pathology and function in a mouse model of Alport syndrome.

Alport syndrome (AS) is a hereditary kidney disorder caused by mutations in COL4A3, COL4A4, and COL4A5, which often lead to progressive renal failure. Although angiotensin II receptor blockers are available for symptomatic treatment, no radical or curative therapies currently exist. Given the genetic basis of AS, exon-skipping therapy has the potential to serve as a definitive treatment. In this study, we established a tamoxifen-inducible exon 21-skipping mouse model, enabling the evaluation of post-onset therapeutic intervention. We generated a novel AS mouse model harboring a patient-derived nonsense mutation (R471*) in exon 21 of Col4a5 on a C57BL/6 background. Using this strain, we further developed a tamoxifen-inducible, podocyte-specific exon 21-skipping model. Induction of exon skipping, either before or after disease onset, restored truncated collagen IV α5 expression, improved renal function, and ameliorated glomerular and tubular pathology. Notably, treatment initiated after the onset of proteinuria reversed glomerular injury, underscoring its therapeutic potential even in progressive stages. This model provides a robust platform for evaluating mutation-targeted therapies and supports the feasibility of exon-skipping approaches for AS and other monogenic kidney diseases.