PATIENT-DERIVED CELL-BASED MODELS FOR THERATYPING AND INDIVIDUAL CFTR MODULATOR ASSESSMENT

Cystic fibrosis (CF) is an autosomal recessive disorder caused by variants in the CF transmembrane conductance regulator (CFTR) gene, which result in abnormal ion and fluid transport across epithelial surfaces in the gastrointestinal and hepato-biliary systems, respiratory tract, reproductive system and sweat glands. New CFTR modulator drugs can lead to profound clinical improvements, but efficacy of such new treatments for rare, especially missense, variants remain mostly unclear and difficult to predict. CFTR gene variants can be classified by the mechanistic impact of the CFTR variant and how this relates to residual function. Furthermore, variants can be classified based on the response to CFTR modulators, which includes functional and biochemical characterization, which is called theratyping. This is followed by theranostics, which uses patient-derived living cells, such as airway or rectal cells, in various culture modalities and assay platforms. These patient-derived model systems can both be used to understand general characteristics of individual variants, but also allow the quantitative interpretation of two variants in an individual genetic background. This allows such model systems to analyze and potentially predict individual responses to CFTR modulators, which is proving to be highly relevant for people who carry rare or ultra-rare variants with an unknown response to treatment. In this chapter the recent developments, advantages and disadvantages of different model systems, in the context of theranostics, are discussed.