FFC#5/2019

Small molecules modulating splicing as novel CFTR amplifier drugs

FFC#5/2019

Small molecules modulating splicing as novel CFTR amplifier drugs.

PRINCIPAL INVESTIGATOR

Stefano Duga (Università Humanitas, Genetica Medica e Biologia dell’RNA, Rozzano, Milano)

Partner

Raffaella Melfi (Dip. Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche, Università di Palermo)

RESEARCHERS

6

CATEGORY

AREA 1 Therapies to correct the underlying defect

DURATION

1 year

GOAL

€ 60.000 €

RESULTS

The researchers measured the actual amount of full-length CFTR mRNA using next-generation sequencing technologies (Nanopore and PacBio) capable of providing the sequence of long nucleic acid molecules (RNA or DNA). This analysis was carried out on samples of different tissues from CF persons (lung, testis, vas deferens, colon and pancreas) and in CaCo2 cells (human intestinal epithelium cell lines used as a model of the intestinal barrier). The project allowed to evaluate the effect of pharmacological intervention with kinetin and its derivative RECTAS, confirming their ability to correct the splicing in model cells CaCo2 and CuFi-1 (bronchial epithelial cell line derived from a person with fibrosis cystic homozygous for the Delta F508 mutation). Researchers characterized the mechanism of action of kinetin/RECTAS confirming a low level of off-target splicing modulation. The researchers would demonstrate the action of kinetin and RECTAS on further disease models (such as intestinal organoids) and they would also evaluate the amplifier effect of kinetin/RECTAS on CFTR protein.

OTHER RESULTS

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

FFC#4/2023

Pseudopaline–aztreonam conjugates exhibited enhanced antimicrobial activity against Pseudomonas aeruginosa compared to aztreonam alone

FFC#10/2023

Several drugs already approved for human use inhibit the growth of P. aeruginosa, its virulence, or its ability to form biofilms in vitro