Patients with cystic fibrosis (CF) very often develop chronic infections caused by Pseudomonas aeruginosa being very difficult to treat. The chronic infection catalyzes insurgence of inflammation, uncontrolled tissue rearrangement and fibrosis, with deadly consequences. The current anti-inflammatory treatments are restricted only to symptomatic control of CF-associated airway inflammation, therefore novel and effective therapeutic options are urgently needed.
The identification of novel therapeutic options to mitigate the inflammation process in CF is the objective of the project. Histone deacetylase 6 (HDAC6) enzyme has been related to the patho-mechanisms associated to inflammation and fibrosis. HDAC6 is therefore an attractive new target to be explored for this aim. Inhibiting its function with small molecules displaying high potency and selectivity could represent an innovative strategy to tackle inflammation and prevent fibrotic damage.

The main activity of the project were:
1) Comparison of known selective HDAC6 inhibitors (HDAC6i) through experimental evaluation of potency, selectivity and pharmacokinetic parameters
2) Design, synthesis, optimization and biological assessment of novel selective HDAC6i;
3) Demonstration of the in vivo efficacy on inflammation and infection in an animal model of chronic Pseudomonas aeruginosa infection in collaboration with the CFaCore (Cystic Fibrosis Animal Core Facility) of FFC Ricerca.

We provided the first in vivo POC of the efficacy of HDAC6 selective inhibition on both the inflammatory and infection associated to CF phenotype using a known inhibitor. In parallel, we have developed a series of novel inhibitors endowed with high HDAC6 selectivity, assessed on both isolated protein and cell-based assays, and favorable pharmacokinetic profile. Our results pave the way to establish a novel therapeutic option for inflammation in CF to be potentially used in combination with correctors of the genetic defect.