Drug discovery for polycystic kidney disease
Polycystic kidney disease is a progressive deadly genetic disease. Current treatment is limited to renal dialysis until a transplant patient becomes available. There is a need for improved therapeutic interventions that can delay or stop the disease progression. Identification of novel medicines requires in vitro test systems that mimic the disease to screen for candidate drugs for polycystic kidney disease. The objective of the project was to develop fluorescent protein reporter cell lines that can be integrated in high throughput imaging-based drug screening approaches. We started a collaboration between Leiden University and OcellO B.V. (currently CrownBiosciences B.V.); the latter would be able to service the test systems for drug discovery.
The disease progression of polycystic disease is associated with changes in the cell biology of renal cells. This is characterized by specific genes that are upregulated during the disease progression. Conceptually, we are aiming to use gene expression as a marker of the extent of the progression of the disease. Within the project we have used existing gene expression data from patients and animal models of polycystic kidney disease to identify genes that are highly expressed when the disease has extensively progressed. Such genes would be excellent markers for identifying drugs that can suppress disease progression. Stem cell technology allows the development of kidney organoids. We have used induced-pluripotent stem cells and have integrated fluorescent markers in these cells to tag our genes of interest so that we could follow under the microscope in stem cell-derived kidney organoids the expression of polycystic kidney disease progression markers.
The project has identified relevant genes using bioinformatics analysis. Subsequently, CRISPR gene editing technology was used to successfully establish functional fluorescent reporter lines that can be used for imaging-based drug screening.
