FFC#24/2015

CFTR-defective biliary cells from human induced pluripotent-stem cells (iPSC) as a model to study the role of innate immunity in cystic fibrosis liver disease

FFC#24/2015

CFTR-defective biliary cells from human induced pluripotent-stem cells (iPSC) as a model to study the role of innate immunity in cystic fibrosis liver disease

PRINCIPAL INVESTIGATOR

Mario Strazzabosco (Dipartimento di Chirurgia e Medicina Traslazionale, Laboratorio di Epatologia – Università degli Studi Milano-Bicocca)

RESEARCHERS

4

CATEGORY

AREA 4 Lung inflammation

DURATION

2 years

GOAL

€ 60.000 €

RESULTS

The researchers obtained from iPSC of CFTR-F508del homozygous patients F508del cholangiocytes reproducing the polarity and the secretory function of the biliary epithelium. PKA/c-AMP mediated fluid secretion was impaired in F508del cholangiocytes and negligibly improved by VX-770 and VX-809, two small molecule drugs used to correct and potentiate ΔF508 CFTR. Moreover, ∆F508 cholangiocytes showed increased phosphorylation of SFK (Src kinase family) and TLR4 and pro-inflammatory changes. Treatment with Src inhibitor (PP2) decreased the inflammatory changes and improved cytoskeletal defects. Inhibition of SFK along with administration of VX-770 and VX-809 successfully restored fluid secretion to normal levels. The study has shown that, in regard of CFLD, targeting Src kinase and decreasing inflammation may increase the efficacy of pharmacological therapies aimed at correcting the basic ∆F508 defect. Moreover it has outlined that iPSC technology can be used to perform studies on the efficacy of new drugs for CFLD and possibly applicable to other organs (i.e. lung, pancreas, intestine).

OTHER RESULTS

FFC #3/2024

Two molecules are effective in activating Heat Shock Proteins and enhancing the action of CFTR correctors with the F508del mutation in vitro.

FFC#5/2024

Some peptide nucleic acids (PNAs) re-sensitise Pseudomonas aeruginosa to the antibiotic meropenem in vitro and reduce its virulence.

FFC#1/2023

Tezacaftor, one of the components of Kaftrio, induces an accumulation of dihydroceramides both in vitro and in vivo in animal models