Development of trimetylangelicin as a treatment for cystic fibrosis

Partners

Integrated University Hospital of Verona, Department of Pathology and Diagnostics, Laboratory of Molecular Pathology
(Group leader: Giulio Cabrini)

University of Bari, Department of General and Environmental Physiology
(Group leader: Valeria Casavola)

University of Ferrara, Department of Biochemistry and Molecular Biology, Section of Molecular Biology
(Group leader: Roberto Gambari)

Disease

Cystic fibrosis

Cystic Fibrosis (CF) is a recessive autosomic disease caused by a defect of CFTR gene. CFTR protein is normally localized in the apical membrane of several epithelial tissues and its main function is the transport of chloride ion, thus indirectly regulating sodium and water transport. The main cause of the reduced life expectancy and life quality of patients suffering from CF lies in the pulmonary effects of the disease. In conductive airways, bronchi and bronchioles, the defect of CFTR protein reduces hydration of surface respiratory secretions and mucociliary clearance, causing a constitutive inflammatory status, thus favoring bacterial infections, caused by Pseudomonas aeruginosa, frequently chronic in the advanced stages of the disease.

Incidence of the disease

The disease affects 1 out of 2.500-3.000 newborns, with 1 healthy carrier out of 25-30 subjects in a general population of Caucasian origin. EMA and FDA include CF in the orphan disease list and more than 5000 living patients are present in Italy, regional prevalence being between 4,4 and 10,4 patients out of 100.000 inhabitants. CFTR gene may be defective because of more than 1.500 different mutations. Phenylalanine deletion in the 508th position on the protein (F508del) is the most frequent mutation, indeed it is present in about 50% of the chromosomes of the patients and causes a molecular defect due to incomplete maturation. CFTR F508del protein, is not correctly located on the apical membrane of epithelial cells involved in the disease, including bronchial epithelium, and has a reduced chloride ion transport capability, thus leading to overt pathological conditions.

 

Project

Rational basis of the project

In order to overcome the limits endowed with the available treatments, namely antibiotics and physiotherapy, active research is going on several molecules, developed with the following aims:

  • to correct the mutated protein (“correctors” of mutated CFTR)
  • to potentiate its reduced activity (“potentiators” of mutated CFTR)
  • to reduce the noxious effects of pulmonary inflammation (new anti inflammatory agents)

Goal of the project 

Preliminary data collected by the partners of this project, some previously published and some not yet published, indicate that some angelicin derivatives, defined psoralens on the basis of their chemical structure, may be active on one or more of these parameters. The compound 4,6,4 '- trimetylangelicin (TMA) has been studied more extensively than the other ones, demonstrating that it is a potent inhibitor of the inflammatory process induced in bronchial epithelial cells by P. aeruginosa and an effective enhancer of CFTR.
TMA has been studied up to now by a collaborative network that includes research groups at the University Hospital of Verona, the Universities of Ferrara, Padua, Bari and the Scientific Institute S. Raffaele in Milan (A. Bragonzi). This line of research has been supported by many grants, including continuous support by the Italian Cystic Fibrosis Research Foundation. Recent findings on the biological activity of TMA recently allowed to file an application for patent protection.
The opportunity to develop this compound and to perform further studies on other compounds of the same family may make available for the treatment of CF innovative agents, active on various parameters altered in disease. The aim of the project is to test in a wide variety of in vitro and in vivo experiments TMA, in order to verify the possibility that it can be used for the treatment of CF and to explore the potential of several analogs of TMA through targeted testing.

Rare Partners will work with the partners of the project, possibly exploring more than one route of administration. The aim of the project is to complete preclinical development of TMA in this indication and proceed with Orphan Drug Designation and preliminary clinical validation in  patients with CF.