Cellular reprogramming is a new and rapidly emerging field where somatic cells can be turned into pluripotent stem cells or other somatic cell types simply by overexpression of specific combinations of genes. This remarkable discovery allows for the generation of patient specific cell lines that will serve as major tools for understanding how diseases arise and develop, and they may also prove useful for drug screens, diagnostics and other biomedical applications.
We have developed a reprogramming technique that directly converts human fibroblasts to functional dopamine (DA) neurons, which is the subtype that is affected in Parkinson’s Disease (PD). This opens up for possibilities to generate therapeutic neurons, including patient specific neurons on demand. These neurons, and the techniques for producing them, will become valuable tools for understanding and treating neurodegenerative diseases such as PD. Direct cell conversion is of particular interest for cell replacement therapy as the reprogramming does not involve a proliferating cell intermediate, and thus the risk of uncontrolled proliferation and tumor formation after transplantation is minimized. This project integrates mechanistic studies based on single cell sequencing to improve the technology and control of cell fate such that a large number of authentic DA neurons are obtained. Induced DA neurons will be generated from individuals with PD and age matched healthy donors and subjected to comparative assessments in vitro and in vivo in order to investigate whether any potential PD-associated pathology emerges in the patient derived cells. This will then guide future decisions regarding autologous vs. allogeneic donors. The cells will be extensively validated using pre-clinical animal models of PD. The studies will include direct comparison with primary fetal and hESC-derived DA neurons on criteria important for clinical use such as midbrain subtype identity and in vivo potency and efficacy.
Fields of science
Funding SchemeERC-COG - Consolidator Grant