Fenretinide in CF: breaking the inflammation/infection vicious
Fenretinide, a synthetic retinoid, is a new chemical entity with a well-documented history of safety in clinical studies involving more than 3,000 adult and pediatric patients, mostly for the prevention and treatment of cancer. In animal model of CF, fenretinide was shown to address the complex links between fatty acids metabolism and inflammatory signaling, which is distinct from the retinoid class mechanism of action. Fenretinide works by correcting the defective metabolism of AA and DHA, and modulates chronic inflammation via a pro-resolving mechanism supported by a strong rationale linked to the expression of the CF genetic defect.
Preclinical research conducted at RI-MUHC in Montreal showed that the oral administration of fenretinide results in correction of the AA/DHA ratio in the lungs of CFTR-knockout mice. Treatment with fenretinide increased the levels of DHA in CFTR-knockout mice, and it brought the levels of AA down to the levels observed in wild-type mice. Normalization of AA/DHA ratios resulted in decreased expression of inflammatory genes normally overexpressed in CFTR-knockout mice (IL- 1β and S100A8) and increased clearance of pulmonary infections with Pseudomonas aeruginosa, the bacterium involved in perpetuating the inflammation-infection vicious cycle in CF. In the same animal model of CF, fenretinide has also shown potential in preventing the early onset of osteoporosis, an increasingly prevalent comorbidity in CF.
Febretinide has a multi-target mechanism of action in CF, usually seen with disease-modifying therapies. It was shown that fenretinide corrects the AA/DHA imbalance and inhibits macrophage inflammatory mediators via the Extracellular signal-Regulated Kinase (ERK) pathway. Fenretinide was also shown to inactivate pro-inflammatory transcriptional nuclear factor (NF)- kappaB, as well as to inhibit the downregulation of Peroxisome Proliferator-Activated Receptor gamma (PPARγ). The proinflammatory response and altered fatty acid metabolism in CF are linked to decreased expression of PPARγ in epithelial cells and PPARα in macrophages.