A new study shows that inhibition of the histone deacetylase (HDAC) enzyme isoform HDAC6 has potential application as a treatment to reduce bacterial load for patients with cystic fibrosis (CF).

The study, published in the European Journal of Pharmacology, details how researchers administered a synthesized compound selected for its ability to inhibit HDAC via aerosol to a mouse model of chronic respiratory infection.

“In this study, we set up an appropriate screening funnel of selective HDAC6 inhibitors and provided the first in vivo proof-of-concept of the efficacy of selective HDAC6 inhibition in contrasting the pro-inflammatory phenotype in a mouse model of P. aeruginosa respiratory infection,” the authors wrote. “Compound 2 demonstrated no toxicity and robust anti-inflammatory profile in a mouse model of P. aeruginosa infection upon aerosol administration.”

Based on current evidence of the involvement of HDAC6 in generating a proinflammatory and fibrotic phenotype in CF, the authors first conducted a literature search for an appropriate compound to inhibit HDAC6. From several possibilities, they selected “compound 2” for their in vivo studies given that, in addition to inhibiting HDAC, it could be synthesized and delivered via aerosol.

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The research team delivered 3 doses of compound 2 via aerosol to a mouse model of P. aeruginosa respiratory infection and assessed its toxicity and anti-inflammatory effects. The results showed a significant and dose-dependent anti-inflammatory effect, leading to reduced total cell counts and neutrophils in bronchoalveolar lavage fluid. Furthermore, at the highest dose of compound 2, key interleukins known to be involved in CF inflammation were significantly reduced.

No adverse effects in terms of cell toxicity, weight loss, or temperature changes in the mice were observed. The authors recommend further study of aerosol HDAC inhibition in mouse models that include additional CTFR mutations and combined therapy to address the complex disease mechanisms in CF.

Reference

Brindisi M, Barone S, Rosse A, et al. Efficacy of selective histone deacetylase 6 inhibition in mouse models of Pseudomonas aeruginosa infection: A new glimpse for reducing inflammation and infection in cystic fibrosis. Eur J Pharmacol. Published online December 5, 2022. doi:10.1016/j.ejphar.2022.175349