Advances in Membrane Therapeutics
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CFTR normally transports chloride ions across epithelial cell membranes; mutated or dysfunctional CFTR lack normal movement of chloride ions across cell membranes, causing clinical manifestations of disease.
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The cystic fibrosis transmembrane conductance regulator (CFTR) forms a chloride channel in cell membranes, creating a pathway for electrolytes and proteins. Normally, CFTR shuttles chloride ions across epithelial membranes of the lung, liver, pancreas, digestive tract, reproductive tract, and skin. Individuals with mutated or dysfunctional CFTR lack normal chloride ion movement across cell membranes, causing the clinical manifestations of cystic fibrosis (CF)—the most common autosomal recessive genetic disease in whites.
“The current standard of care relies on managing cystic fibrosis symptoms, but CFTR repair therapies that treat the underlying channel defect may open a new era of CFTR therapeutics,” says UAB pulmonologist Steven M. Rowe, MD. Several investigational therapies are designed to improve CFTR channel function, restore ion transport, or correct channel processing by manipulating channel maturation to the cell membrane surface.
Scientists have identified more than 1500 CFTR mutations. The most common, DF508 CFTR, is responsible for 70% of defective alleles and is found in 90% of whites with CF. In individuals with this mutation, the protein is misfolded and does not move to the cell surface.
UAB pediatric pulmonologist John Paul Clancy, MD, will direct a national clinical trial investigating VX-809, a DF508 CFTR processing corrector. Vertex Pharmaceuticals manufactures the agent, which is designed to bring mutant CFTR protein to the cell surface. If effective, VX-809 may increase chloride transport across the cell membrane and ameliorate disease.
Interim results from a clinical trial conducted at UAB and Children’s Hospital of Alabama validate CFTR as a viable therapeutic target, says Rowe, who is principal investigator for a trial of another investigational drug, VX-770. Also manufactured by Vertex, VX-770 is a CFTR potentiator that activates ion transport across mutant CFTR channels already localized to the cell surface. UAB was 1 of 14 centers to examine the ability of VX-770 to target CFTR and improve channel function. “Early phase 2 outcomes yielded promising results,” Rowe says. “CFTR activity was restored as measured by sweat chloride analysis and nasal potential difference [NPD] measurements, assays that can differentiate levels of CFTR function. Lung function, a major clinical indicator in CF patients, also improved considerably.”
This is the first therapeutic agent to reduce the high sweat chloride levels in persons with CF. VX-770 may open chloride channels in patients with the G551D mutation, whose CFTR reaches the cell surface but remains dysfunctional.
Rowe and Clancy are investigating an additional compound designed to correct truncated forms of CFTR. A phase 2 trial sponsored by PTC Therapeutics evaluated the ability of PTC124 to promote production of full-length CFTR. Results indicated improvement in CFTR function as measured by NPD and a trend toward improved lung function (Lancet. 2008;372[9640]:719-727). In 2009 Rowe will lead further testing of this new compound.
“Rather than treating late-stage manifestations as we do with traditional therapies for CF, new options address the mutant protein as a potential target,” Rowe says. “Improved treatment of underlying disease may alter progression, improving quality of life and longevity for people with CF.”
For more information contact Dr. Steven Rowe or Dr. John Paul Clancy at 1-800-UAB-MIST or at mist@uabmc.edu.