講演情報
[S15-4]小児のnephrogenomics: Alport症候群における治療戦略
○堀之内 智子, 野津 寛大 (神戸大学大学院 医学研究科 内科系講座 小児科)
Alport syndrome (AS) is a progressive hereditary kidney disease accompanied by hearing loss and ocular abnormalities. There are three types of AS depending on the inheritance mode: X-linked AS (XLAS), autosomal recessive AS, and autosomal dominant AS. XLAS is caused by variants in COL4A5, which encodes the type IV collagen α5 chain, while ADAS and ARAS are caused by variants in COL4A3 or COL4A4, which encode the type IV collagen α3 and α4 chains, respectively. The carboxyl-end non-collagenous (NC) domain is known to be important in type IV collagen to form both triple helices by α3-4-5 chains and a tight network in glomerular basement membrane by these trimers.
The genotype-phenotype correlation in male patients with XLAS is well established; patients harboring non-truncating variants (NC domain conservative) exhibit milder phenotypes compared with those in patients harboring truncating variants. Although conventional ACEI/ARB treatments are certainly effective, the development of more effective therapy is desired, especially for patients exhibiting severe symptoms associated with truncating variants. As a disease-specific custom-made treatment, we reported that in an AS mouse model harboring a truncating variant, exon skipping of the mutated exon using an antisense oligonucleotide may significantly improve the renal prognosis. The favorable prognosis by the preservation of the NC domain is the basic concept of exon skipping therapy. We are now working on the clinical applications in patients with AS and search for diseases where the same strategy can be used.
The genotype-phenotype correlation in male patients with XLAS is well established; patients harboring non-truncating variants (NC domain conservative) exhibit milder phenotypes compared with those in patients harboring truncating variants. Although conventional ACEI/ARB treatments are certainly effective, the development of more effective therapy is desired, especially for patients exhibiting severe symptoms associated with truncating variants. As a disease-specific custom-made treatment, we reported that in an AS mouse model harboring a truncating variant, exon skipping of the mutated exon using an antisense oligonucleotide may significantly improve the renal prognosis. The favorable prognosis by the preservation of the NC domain is the basic concept of exon skipping therapy. We are now working on the clinical applications in patients with AS and search for diseases where the same strategy can be used.