Compelling new support has been provided for histone deacetylase isoform 6 (HDAC6) as a common thread in the generation of the dysregulated proinflammatory phenotype in cystic fibrosis (CF). HDAC6 also plays a crucial role in bacterial clearance or killing as a direct consequence of its effects on CF immune responses. Inhibiting HDAC6 functions thus eventually represents an innovative and effective strategy to tackle multiple aspects of CF-associated lung disease. In this study, we provided the first in vivo PoC of the efficacy of a selective HDAC6 inhibitor in contrasting the CF-associated proinflammatory phenotype and effectively reducing bacterial load in treated animals. First, we embarked a careful compound selection by performing a thorough analysis of scientific literature and relevant patents in the field. We thus identified compound 1 as the most suitable candidate to be engaged in in vivo PoC studies based on its high HDAC6 inhibitory potency and relevant selectivity over other HDAC isoforms. We re-profiled compound 1 in house on its HDAC1/6 potency and its ability in selectively increasing levels of acetylated tubulin in HeLa and A549 cells. Compound 1 demonstrated no toxicity in mouse and was able to dose-dependently reduce the total cell counts and neutrophils in bronchoalveolar lavage fluid (BALF), when locally administered (5, 10 and 20 mg/kg) in a mouse model of chronic Pseudomonas aeruginosa (PA) infection using a Penn-Century MicroSprayer® Aerosoliser. We also performed a cytokines/chemokines profiling by Bioplex assay, which highlighted relevant changes in the levels of interleukins (eg. Il-1a, IL-1b, IL-6) and other inflammatory markers, thus confirming the potential of 1 in effectively reverting the pro-inflammatory phenotype. Moreover, we proved that 1 is able to reduce bacterial load in the same model at the three tested doses, as determined by the reduction of colony-forming units . Quantitative determination of 1 in plasma samples collected from treated mice showed that the compound is not distributed in the body even after a 7-day treatment, thus supporting the safe profile of 1 in our administration settings. Our data pave the way to the development of novel HDAC6 inhibitors specifically tailored for chronic administration in CF patients, thus improving the CF-associated inflammatory phenotype and promoting an effective immune response against infections.

First in vivo proof-of-concept for the efficacy of selective HDAC6 inhibition in cystic fibrosis: Anti-inflammatory profile, effects on bacterial load, formulation, and biodistribution studies

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