Cystic Fibrosis Disease Modelling

Topics

Personalized medicine for CF: matching which therapeutic regimens is effective for which CFTR genotypes and persons with CF, using patient-derived intestinal organoids (PDIOs) in functional assays. Whilst this model has proven already highly valuable, we continue with further optimizations, including:

• Making the model animal-free by replacing Matrigel and animal-product dependent growth factors
• Developing an automated pipeline using robotics for the functional assays, in collaboration with AI and Automation.
• Ultimately, we hope and expect that all improvements contribute to our goal of obtaining official EMA-approval for the FIS assay as CF diagnostic tool

For ultimate preclinical-clinical collaboration, we interact with clinicians Kors van der Ent & Karin de Winter – de Groot at Pediatric Pulmonology.

Addressing academic questions using PDIOs, ranging from characterization of novel treatment regimens (small-molecule based or gene therapy based) or more fundamental questions about CFTR biology. Examples:

• Roughly 10% of people with cystic fibrosis (CF) face a significant unmet clinical need, often due to challenging mutations such as nonsense mutations. We currently characterize various readthrough strategies for treating these mutations and furthermore investigate the safety and fidelity of readthrough approaches using state-of-the-art quantitative proteomics to assess potential off-target effects at the protein level.
• Various gene therapy strategies are studied in the context of CF. One that could be highly effective across a range of CFTR genotypes is generation of suppressor CFTR mutations, which out-cancel the original malignant CFTR mutation.
• People with CF seem to hold an increased chance of developing CRC based on epidemiological and preclinical mouse data. To generate more knowledge on this, we investigate to what extent CFTR has a function as tumor-suppressor gene in intestinal organoids.