Israeli drug offers real hope to cystic fibrosis patients

Novel approach designed by Hadassah researchers tailors drug to specific genetic mutation.

doctors 224.88 (photo credit: )
doctors 224.88
(photo credit: )
An experimental oral drug designed by Hadassah Medical Organization researchers has proved successful in clinical studies for treating most of the Israeli cases of the incurable genetic disease cystic fibrosis (CF). The success of the Phase II trial was announced on Tuesday by Hadassah in Jerusalem and PTC Therapeutics in the US. The drug is a compound called PTC124, which helps to "rescue" the faulty proteins that lead to CF and other illnesses. The drug holds promise in treating more than 2,400 genetic diseases caused by a certain class of DNA mutation. Initially, PTC124 given to mice models of human CF restored to normal function up to 29 percent of the cases of abnormal CF protein. CF affects the mucus glands of the lungs, liver, pancreas and intestines, causing progressive disability due to multisystem failure. The diagnosis of CF may be carried out in fetuses and confirmed in newborns if high levels of salt are found during a sweat test, although some false positives may occur. Most CF victims die in their 20s and 30s from lung failure, but some survive to 40 or 50 years due to lung transplants and other treatments. The experimental drug was previously shown in experiments to be effective in treating up to 25% of the missing or abnormal protein function in mice with Duchenne muscular dystrophy (according to findings which were published in Nature last year). The efficacy in Phase II studies against CF was shown in a report published last week in the prestigious journal The Lancet. The drug is based on the work of Prof. Eitan Kerem, head of pediatrics at Hadassah University Medical Center on Jerusalem's Mount Scopus, and Dr. Michael Wilshansky, head of the pediatric gastroenterology unit. Hadasit, Hadassah's intellectual property arm, negotiated an agreement between Hadassah and PTC, which produces the drug. CF patients lack the CFTR protein, which preserves the level of moisture in lung tissue, the pancreas, the liver and other organs. In patients with a "nonsense" mutation, the process is halted before it is completed, and mucous is not created. People with this mutation constitute 10% of CF patients in the world - but in Israel, they represent most of the patients. Kerem said that 23 adult CF patients, the vast majority of whom have a severe form of the disease with poor respiratory and pancreatic function and recurring lung infections, took part in the Phase II trial. Kerem said the patients had increased production of the missing protein, and more than half reached a normal level after the first two weeks. Their lung function improved, and they also gained weight. "The clinical trial demonstrates the potential for a drug customized to the patient and developed specially to treat people suffering from a specific mutation. The publication in The Lancet offers these patients hope and opens the way for lengthening the drug's range of efficacy and safety," added Kerem. "We hope the drug will be able to treat other diseases caused by the mechanism responsible for this mutation." Recently, Prof. David Bedwell at the University of Alabama at Birmingham said after conducting research on CF mice that "PTC124 is capable of suppressing 'nonsense' mutations‚ that cause cystic fibrosis." A gene that carries a nonsense mutation produces a shortened or faulty protein that degrades in the body. The absence of that protein is what leads to disease, Bedwell said. An estimated one-third of gene defects responsible for human disease are thought to come from nonsense mutations. In the case of CF, the absence of a certain protein leads to an imbalance of salt and water in the linings of the lungs and other membranes. PTC Therapeutics reported that the compound has been granted "orphan-drug" status by the US Food and Drug Administration for the treatment of Duchenne muscular dystrophy and CF, a special status which the government grants in support of drugs for rare diseases.