SCIENCE

Targeting inflammation resolution, a new therapeutic paradigm using the body’s own ability to modulate inflammatory responses, thus controlling inflammation without inducing immunosuppression
(a “pro-resolving” effect).

 

 

LAU-7b as pro-resolving of inflammation and CFTR stabilizer in Cystic Fibrosis

Cystic Fibrosis (CF) is the most common fatal hereditary disease among Caucasians, affecting an estimated 75,000 people worldwide. CF is caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR), a protein that acts as a chloride channel. Over 2,000 mutations have been described in the CFTR gene, the most common of which is △F508. The disruption of chloride and sodium transport results in dehydration of mucus secretions in exocrine tissues, mainly the respiratory tract, pancreas, gastrointestinal tract, and sweat glands. The negative effects caused by CFTR gene mutations are not restricted to ion channels, but also extend to dysfunction of the immune-inflammatory response, resulting in hyperinflammation of the lung and inability to defend against opportunistic infection. Although inflammation is needed to fight infection, an imbalance between pro-inflammatory versus anti-inflammatory environment can lead to an overwhelming and self‐perpetuating inflammatory response that results in lung damage and respiratory failure over time.

Current anti-inflammatory therapies failed to show effect in CF, either because their questionable benefits or due to concerns over their immune-suppressive potential. There are no drugs approved for treating lung inflammation in CF, yet aberrant inflammation is at core of lung degradation and the primary cause of mortality in these patients.

LAU-7b is a novel once-a-day oral form of fenretinide, under development by Laurent Pharmaceuticals for its potential to control inflammation without inducing immune-suppression. As opposed to typical anti-inflammatory drugs, which all work by inhibiting various activation mechanisms of the pro-inflammatory Arachidonic Acid (AA) cascade, LAU-7b is believed to trigger the resolution phase by acting on the docosahexaenoic acid (DHA) pathway, a more natural way to terminate inflammation without affecting its immune response (a “pro-resolving” effect). The imbalance between DHA and AA metabolism is known to be one of the hallmarks of the CF disease, consistent with the inability to make the transition between the activation phase and the resolution phase of inflammation.

Preclinical research 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.

More recent data (Hanrahan 2018) showed fenretinide’s ability to also enhance membrane sphingolipid rafts and stabilize CFTR channel in airway epithelial apical membrane, especially under cellular stress induced by inflammation. The effect on the CFTR function is potentiated when fenretinide is combined with a CFTR corrector, thus demonstrating the important link between inflammation and the basic defect in CF. Furthermore, Radzioch et al. (2018) showed LAU-7b potential to modulate the mucin secretion and preventing the development of age-related pulmonary hyper-inflammation and epithelial hyperplasia in CFTR-KO mice.

REFERENCES