Faculty Affairs and Academic Programs
Gloria Yiu
Medical; Health Sciences; Nursing
Correcting Blau Syndrome at its Genetic Source
Blau syndrome (BS) is a rare monogenic autoinflammatory disease classically marked by granulomatous uveitis, symmetric arthritis, and dermatitis, yet growing reports indicate broader systemic immune dysregulation[1,2]. Although granulomas have suggested a monocyte/macrophage–driven process, emerging data implicate a T cell intrinsic role[3,4]. BS arises from single–base-pair variants[5] in CARD15/NOD2 that trigger hyperinflammation and granuloma formation, leading to vision loss and disability. The single-nucleotide variants that cause BS make the disease an excellent candidate for adenine base-editing therapy[6]. This project will aim to generate human cell lines and patient-derived induced pluripotent stem cells (iPSCs) carrying known BS variants to define variant-specific cellular phenotypes across monocyte/macrophage and lymphoid lineages. Using an established artificial thymic organoid platform, we will dissect how BS mutations perturb thymopoiesis and T cell repertoire development. In parallel, we will design and test base editors to restore NOD2 signaling and normalize inflammatory responses, first in engineered lines, then in patient iPSC-derived hematopoietic cells and primary cells. Building on ongoing proof-of-concept studies, we propose ex vivo correction of patient hematopoietic stem cells followed by autologous transplantation, an approach that has shown safety and efficacy[7]. Outcomes will deliver mechanistic insight into T cell contributions to BS, quantitative assays for pathogenicity and therapeutic rescue, and a preclinical pipeline for a precision, potentially curative, base-editing therapy.
