講演情報
[III-TLR-2]Recapturing Genetic Cardiomyopathy Pathophysiology Using wild-type human iPSC-derived Cardiomyocytes Combined with AAV Vectors
○Hideki Uosaki1,2,3,4, Fuad Gandhi Torizal1, Takeshi Tokuyama1,2, Tatsuya Anzai5, Mitsuru Seki5 (1.Division of Functional Biochemistry, Department of Biochemistry, Jichi Medical University, Tochigi, Japan, 2.Division of Regenerative Medicine, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan, 3.Center for Gene Therapy Research, Jichi Medical University, Tochigi, Japan, 4.Center for Development of Advanced Medical Technology, Jichi Medical University, Tochigi, Japan, 5.Department of Pediatrics, School of Medicine, Jichi Medical University, Tochigi, Japan)
キーワード：
Cardiomyopathy、iPS cells、Disease Modeling
Cardiomyopathies are a leading cause of heart failure and sudden death from infancy through adolescence. While induced pluripotent stem cells (iPSCs) are promising for studying genotype-phenotype correlations, their laborious nature limits scalability across diverse genetic variants. Here, we established a streamlined approach to recapitulate cardiomyopathy pathophysiology in wild-type iPSC-derived cardiomyocytes (iPSC-CMs) by transducing pathogenic variants via adeno-associated virus (AAV). We modeled sarcomere and non-sarcomere variants, successfully capturing phenotypes for dilated (DCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathies. Structural analysis revealed that DCM variants caused sarcomere disarray and thinning, while HCM variants induced cellular enlargement. Specifically, DCM variants of LMNA altered nuclear morphology and reduced sarcomere expression. Functional contractility analysis identified disease-specific signatures, for instance, reduced contraction in DCM models and prolonged relaxation in HCM and RCM models. This on-demand system facilitates rapid therapeutic testing; for example, the myosin ATPase inhibitor mavacamten improved relaxation in HCM models. Our AAV-hiPSC-CM platform enables quantitative structural and contractile analysis across various genotypes and is easily adaptable for multiplexed disease arrays.
