Grant: Proof of Principle Program - Phase I

Cystic Fibrosis is the most common lethal genetic disease in Caucasians. Chronic infection in CF patients leads to fibrosis, gradual deterioration in lung function, and death. Although the lifespan of a CF patient has increased to 37 years, the deterioration in lung and digestive function results in lower quality of life for patients and increased health care costs for society. CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene that encodes for a chloride ion channel expressed on the apical surface of epithelial cells. The most frequent CFTR mutation is a phenylalanine deletion, which is present in 90 percent of CF patients. The delta F508CFTR protein is misfolded and retained in the endoplasmic reticulum, where is it rapidly degraded. Misfolding of delta F508CFTR is thought to be reversible and it is estimated that only 10 to15 percent of the ER retained delta F508CFTR needs to traffic to the plasma membrane to restore CFTR function in CF patients. Therefore, therapies that even partially correct the effects of this mutation are expected to benefit most CF patients. Thomas and Hanrahan at McGill have used a cell based assay for correctors of the delta F508CFTR trafficking defect to screen Andersen's library of marine invertebrate extracts. From this screen, the marine sponge alkaloid latonduine A was found to be a potent corrector of delta F508CFTR trafficking that results in functional ion channel expression on the cell surface. It is non toxic in cells and effective at correcting the delta F508CFTR trafficking defect in intestinal tissue isolated from CF mice. It was also orally active and shows no toxicity in a CF mouse salivary secretion assay. This data indicates that latonduine A is a promising drug candidate for treating Cystic Fibrosis. The CIHR POP grant funds will be used to further evaluate the clinical potential of latonduine A.