Periodic Reporting for period 4 - DiRECT (Directly reprogrammed renal cells for targeted medicine)
Período documentado: 2023-09-01 hasta 2025-02-28
Millions of people worldwide suffer from kidney disease. However, many of these conditions remain difficult or impossible to treat. One of the main obstacles to developing new treatments is the lack of reliable and representative model systems to study the underlying mechanisms or to test therapeutic strategies. In previous work, we demonstrated that the expression of four transcription factors can reprogram fibroblasts (skin cells) into kidney tubular-like cells. This form of cellular direct reprogramming, potentially applicable to patient-specific cells, offers a powerful tool to investigate the origins of kidney disease, improve the evaluation of novel treatments, and screen for nephrotoxic side effects of new drugs.
The DiRECT project achieved substantial progress in understanding molecular disruptions that occur in kidney diseases. These include congenital anomalies of the kidney and urinary trackt (CAKUT), which is frequently caused by mutations in the gene HNF1B, but also autosomal dominant kidney disease (ADPKD) and Renal Fanconi syndrome. The use of directly reprogrammed cells was essential to uncover new molecular defects in these conditions. Using single cell RNA-Sequencing and various analysis, we gained insights into the reprogramming process at the cellular level. This allowed us to improved the reprogramming protocol to make it more robust, better at converting human cells and thus easier to use.
Our experiment required us also to find new technological solutions to achieve these results. This led us to develop new microscopy techniques, image analysis pipelines and new genome engineering protocols, for which a patent was filed. In total, we published 17 peer-reviewed articles in prestigious scientific journals, presented our work at numerous conferences, but also engaged in activities to present our results to the genearal public, such as the Scientifica (Zurich Science Fair).
Our experiment required us also to find new technological solutions to achieve these results. This led us to develop new microscopy techniques, image analysis pipelines and new genome engineering protocols, for which a patent was filed. In total, we published 17 peer-reviewed articles in prestigious scientific journals, presented our work at numerous conferences, but also engaged in activities to present our results to the genearal public, such as the Scientifica (Zurich Science Fair).
The DiRECT project achieved substantial advances in demonstrating that direct reprogramming is a feasible and versatile method to generate kidney tubular-like cells that have unique properties. We showed that these cells are highly useful to uncover disease mechanisms and mimic kidney disease in the dish. We expect, that the direct reprogramming method will further enhance research on kidney diseases causes, tailor kidney disease treatments to individual patients or make specific predictions on which substances may pose a risk to persons more sensitive to drug induced kidney failure.