Project
Combinatorial, High-throughput organoid screens for personalized medicine
Perspectives for patients with cystic fibrosis (CF) have dramatically changed over the last few years, with the advent of CFTR modulators, a new treatment class comprising several mutation-specific drugs. Recent drug development efforts are directed to the most frequent CFTR mutation (F508del) and a handful of less frequent mutations, excluding around 10% of patients with only rare mutations, who depend on academic research innovation and public-private partnerships to provide efficient treatments. For these patients, current personalized medicine approaches are labor and cost intensive. Therefore, innovations increasing the throughput paralleled by a reduction in sample size and reagent volumes, would be of great economical and societal value. In this project, we will investigate, on biobanked rectal organoids of ~70 CF patients with rare mutations ineligible for licensed drugs: (1) Novel combinations of CFTR modulators, approved or in late development phase, in their ability to restore CFTR function (2) For mutations not rescuable by compounds, we will develop tailored CRISPR-Cas-based gene editing strategies. To scale up the process, we will develop a novel microfluidic High-Throughput Screening (HTS) platform, with increased test capacity on smaller organoid samples, opening up avenues for rapid and ex-vivo HTS for drug and gene editing therapies in a personalized medicine approach.