Using iPSCs as a tool to model and treat genetic disorders
We have been interested in the reprogramming of somatic cells into pluripotent stem cells and the differentiation of these induced pluripotent stem cells (iPSCs) into different cell types since 2007. Our research focuses on the use of iPSCs to treat and model, monogenic as well as complex genetic disorders. We believe that human iPSCs are a great tool to study genetic disorders with a heterogeneous phenotype as they enable direct linkage of the patient’s phenotype to the observed in vitro phenotype. For this we utilize our expertise in the differentiation and the genetic modification of human iPSCs. W have generated human thymus epithelium from human iPSCs as a proof-of-concept for the treatment of DiGeorge syndrome patients (Chhatta et al, JACI 2019). In addition, we have created an iPSC-based model for RAG2-severe combined immunodeficiency (SCID), a disorder in which the patients do not develop an acquired immune system. In contrast to the murine situation, we demonstrated a progressive differentiation block during the early phases of human thymic T cell development in RAG-2 deficient patients that can be rescued using gene editing (Themeli et al. Stem Cell Rep. 2020). In 2018 the group’s research focus has started to switch to the modelling of neural disorders. One project is on the modeling of complex genetic microdeletion and microduplication syndromes with a broader, but incompletely penetrating phenotypes. We take advantage of these iPSCs with multiple number variants (CNVs) to identify the genes responsible for specific phenotypes using amongst others iPSC-derived cerebral organoids (Figure 1). The other research line, which was recently initiated in collaboration with Prof. F. Baas (dept of Human Genetics) with help of the ForWis(h)dom foundation and Stichting GNAO1 NL, is to study the neural disorder GNAO1. Patients with a pathogenic variant of GNAO1 suffer from early onset epileptic seizures, progressive hyperkinesia, and cognitive and motor developmental delays. GNAO1 patients respond generally poorly to the available drugs and may die prematurely. Our goal is to identify the mechanisms underlying this disease and improve treatment modalities.
Fig.1 iPSC-derived cerebral organoid.