Efficacy of Rhesus Theta ({theta})-Defensin-1 in Experimental Models of Pseudomonas aeruginosa Lung Infection and Inflammation [PublishAheadOfPrint]

Rationale: Chronic airway infection and inflammation contribute to the progressive loss of lung function and shortened survival of patients with cystic fibrosis (CF). Rhesus theta () defensin-1 (RTD-1) is a macrocyclic host defense peptide with antimicrobial and immunomodulatory activities. Combined with favorable preclinical safety and peptide stability data, RTD-1 warrants investigation to determine its therapeutic potential for treatment of CF lung disease.

Objectives: We sought to evaluate the therapeutic potential of RTD-1 for CF airway infection and inflammation using in vitro, ex vivo, and in vivo models.

Methods: We evaluated RTD-1's effects on basal and P. aeruginosa induced inflammation in CF sputum leukocytes and CF bronchial epithelial cells. Peptide stability was evaluated by incubation with CF sputum. Airway pharmacokinetics, safety and tolerance studies were performed in naïve mice. Aerosolized RTD-1 treatment effects were assessed by analyzing lung bacterial burden and airway inflammation using an established model of chronic P. aeruginosa endobronchial infection in CF (F508) mice.

Measurements and Main Results: RTD-1 directly reduces metalloprotease activity, as well as inflammatory cytokine secretion from CF airway leukocyte and bronchial epithelial cells. Intrapulmonary safety, tolerability and stability data support the aerosol administration route. RTD-1 reduced bacterial lung burden, airway neutrophils, and inflammatory cytokines in CF mice with chronic P. aeruginosa lung infection.

Conclusions: Collectively, these studies support further development of RTD-1 for treatment of CF airway disease.

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