Harnessing iPSCs,3D organoids,and multiomics to model rare vascular diseases: Emerging new approach methodologies

Abstract

Rare vascular diseases are a diverse group of life-threatening conditions defined by their low prevalence but profound impact on patient morbidity and quality of life. Diagnosing these disorders remains a significant clinical challenge due to their genetic heterogeneity, overlapping phenotypes, and limited patient populations. As such, the development of robust and human-relevant disease models is critical for elucidating pathogenic mechanisms and guiding therapeutic discovery. The advent of human induced pluripotent stem cell (iPSC) technology has opened new avenues for modeling rare vascular diseases by enabling the generation of patient-specific vascular cell types, including endothelial cells, smooth muscle cells, and fibroblasts, and the creation of both two-dimensional cultures and three-dimensional vascular organoids. Together with genome editing and next-generation multiomics, these platforms represent new approach methodologies (NAMs) that allow for detailed investigation of disease biology, facilitate the correction of pathogenic mutations, and enable high-throughput drug screening in a personalized context. In this review, we highlight the advancements in iPSC-derived vascular modeling, discuss the integration of gene editing and multiomics technologies, and explore their transformative potential for uncovering mechanisms and developing precision therapies for rare vascular diseases.