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 has been oriented towards 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 (1, 2, 3). Current research focuses on the GNAO1-associated neural developmental disorder. The GNAO1-associated disorder is a rare disorder caused by mutations in only 1 of the GNAO1 gene copies. According to our recent data 1:100,000-200,000 newborns have symptoms caused by GNAO1-variants (4). Patients with a pathogenic variant of GNAO1 display a diverse array of symptoms including epileptic seizures, which often belong to the group of developmental and epileptic encephalopathy (DEE), progressive movement disorders, and cognitive and motor developmental delays. GNAO1 patients respond generally poorly to the available mediation and about 10% of the patients die prematurely. Our goal is to identify the mechanisms underlying this disorder and improve treatment modalities through iPSC-based research.
Current research is funded by the ForWis(h)dom foundation, Stichting GNAO1 Nederland ( www.gnao1.nl ), and the Bow foundation (www.gnao1.org)
A selection of relevant publications:
- Chen, X., Janssen, J. M., Liu, J., Maggio, I., 't Jong, A. E. J., Mikkers, H. M. M., & Gonçalves, M. A. F. V. (2017). In trans paired nicking triggers seamless genome editing without double-stranded DNA cutting. Nature communications, 8(1), 657. https://doi.org/10.1038/s41467-017-00687-1
- Chhatta, A. R., Cordes, M., Hanegraaf, M. A. J., Vloemans, S., Cupedo, T., Cornelissen, J. J., Carlotti, F., Salvatori, D., Pike-Overzet, K., Fibbe, W. E., Hoeben, R. C., Mikkers, H. M. M., & Staal, F. J. T. (2019). De novo generation of a functional human thymus from induced pluripotent stem cells. The Journal of allergy and clinical immunology, 144(5), 1416–1419.e7. https://doi.org/10.1016/j.jaci.2019.05.042
- Themeli, M., Chhatta, A., Boersma, H., Prins, H. J., Cordes, M., de Wilt, E., Farahani, A. S., Vandekerckhove, B., van der Burg, M., Hoeben, R. C., Staal, F. J. T., & Mikkers, H. M. M. (2020). iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests. Stem cell reports, 14(2), 300–311. https://doi.org/10.1016/j.stemcr.2019.12.010
- M. Sáez González, K. Kloosterhuis, L. van de Pol, F. Baas, H. Mikkers (2023). Phenotypic Diversity in GNAO1 Patients: A Comprehensive Overview of Variants and Phenotypes. Human Mutation. https://doi.org/10.1155/2023/6628283
PhD theses from lab alumni:
- Tobias Messemaker “Exploring the world of non-coding genes in stem cells and autoimmunity https://openaccess.leidenuniv.nl/handle/1887/61075
- Amiet R. Chhatta “Novel Regenerative Therapies for the Adaptive Immune System”
