Researchers report the generation of cell models using airway epithelial stem cells (AESC) from patients with different genotypes. Three different models were generated: I) differentiated 2D monolayers for biochemical evaluation of CFTR mRNA and protein; ii) 3D organoids for forskolin-induced swelling (FIS); iii) Air Liquid Interface (ALI) culture of respiratory tissue for fluid reabsorption and current measurements. Each patient-specific cell model were tested to evaluate the efficacy of drugs available for the treatment of CF. Models from homozygous patients for F508del mutation showed an increase in CFTR activity with Trikafta treatment, but moderate response to Orkambi and Symdeco. In cell models obtained from heterozygous patients carrying F508del and a mutation with residual function or unknown function, Trikafta showed a relative increase, while models from individuals with rare genotypes did not show satisfactory response to Orkambi or Symdeco, and the evaluation of the efficacy of Trikafta is currently in progress. These cellular models could be used to customize drug or gene therapy (personalized therapy) according to the patient’s genotype. In addition, these models could also be effective for patients carrying rare variants.
Regarding modifications of the CFTR with gene editing, the researchers developed an assay to quantify the number of copies of the modified gene, necessary to evaluate the efficacy of gene correction. Further cell models from rare variants, pharmacological tests and the development of the gene-editing strategy are the subject of the extension of this project, the FFC#8/2020.