FFC#10/2022

Towards the development of GY-971a as anti-inflammatory drug in cystic fibrosis

FFC#10/2022

GY971a has demonstrated anti-inflammatory activity without showing toxicity either in vitro on cells or in vivo models

RESEARCHERS

12

CATEGORY

AREA 4 Lung inflammation

DURATION

2 years

GOAL

€ 117.750 €

RESULTS

Due to previous studies, the molecule GY971a (mesylate salt of GY971) was selected from a large library of 4,6,4′ trimethylangelicin (TMA) derivative compounds and was shown to be effective as an anti-inflammatory agent. Therefore, it may be an excellent candidate for preclinical development for the treatment of cystic fibrosis (CF) lung disease.

To test the compound, in vitro models of bronchial epithelial cell lines and ex vivo models of bronchial cells derived from people with CF with the F508del mutation on both copies of the CFTR gene were used. These cells were provided by FFC Ricerca’s Primary Culture Service. In vivo studies were conducted in animal models using FFC Ricerca’s CFaCore service.

The cells were treated with different concentrations of GY971a, ibuprofen, the antibiotic Tobramycin and Kaftrio, to study the efficacy of the molecule compared and/or in combination with each of these drugs used in therapy, and several markers of lung inflammation were monitored.
In vivo studies were instead conducted by CFaCore in animal models: GY971a was administered via aerosol to mice with induced lung inflammation.
The data obtained demonstrate in all the used biological models that GY971a possesses anti-inflammatory activity and does not cause cytotoxic (i.e. toxic effects on cells) in vitro and ex vivo, or hepatotoxicity in vivo. Furthermore, it does not interfere with the action of CFTR-modulating drugs.

The results from experiments in ex vivo models confirm those obtained in simpler cell lines, and show that even on cells derived from people with CF the investigational compound has significant efficacy, although some variability in response was found.
In vivo, in the acute animal inflammation model, GY971 was also effective in decreasing the concentration of neutrophils (immune system cells involved in inflammation) and specific markers of inflammation.

The research will continue with the new project FFC#11/2024, during which the efficacy and potential side effects of GY971, either alone or in pharmaceutical form, will be verified through in silico, in vitro, ex vivo analysis on bronchial and nasal cells, and in vivo analysis on mice and zebrafish.

In November 2024, the European Medicines Agency (EMA) granted orphan drug designation for cystic fibrosis to GY971a, a prerequisite to start the eventual industrial pharmaceutical development of GY971 for the treatment of cystic fibrosis.

OTHER RESULTS

FFC#1/2023

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