Due to the inaccessibility of human brain cells for molecular research, neurodegenerative diseases have mostly been studied in animal and simplified cellular models, which have significantly broadened our knowledge, but have drawbacks limiting successful translational research. We aim to address this gap by developing human model systems based on patient-derived induced pluripotent stem cells, which have the genetic configuration of the patients and allow differentiating and studying somatic cell types directly affected by disease, such as neurons, glia or endothelial cells. In addition, these models are accessible for genetic manipulation and amenable to drug development, which facilitates molecular studies with disease-affected human cell types and can accelerate the identification of novel therapeutic approaches.
We have recently developed efficient technologies to introduce and remove patient mutations in human induced pluripotent stem cells using the CRISPR/Cas9 gene editing system and have also developed protocols for the optimized differentiation of neuronal and glia cell types of the human brain. We have applied these technologies to generate and study isogenic sets of human neurons with mutations in disease-associated genes, such as APP, PSEN or TAU.
We aim to further optimize the genetic configuration, cell type composition and culture parameters of these and further models to elicit the most disease-relevant phenotypes, and then exploit them to reveal molecular disease mechanisms.
Contact: Prof. Dr. rer. nat. Dominik Paquet