Medicine: Attacking Cystic Fibrosis
Hadassah’s Cystic Fibrosis Center treats one in every five Israelis who suffers from the genetic disorder, helping with daily care—and searching for a cure.
The group had already met several times when it happened. Like any support group, its members had bonded quickly, taking comfort in being with others who understood. The youngsters didn’t seem unusually brittle or agitated that day. But when the social worker turned to one teen, the girl burst out: “I wish he’d die! May the Almighty forgive me, I wish that my brother would die!”
As she collapsed in weeping, other kids there spoke up, some in voices hushed with guilt, others angry and defiant. “I know exactly what you mean,” one child said.
“It is something I think every day, but never dare put in words. I feel I’m wicked and unnatural even thinking like this,” another added.
“It was a critical moment,” says Shifra Kurtz, the social worker who leads cystic fibrosis support groups for siblings and parents, part of the Cystic Fibrosis Center at the Hadassah–University Hospital at Mount Scopus. “It was a chance to help these sad, burdened youngsters see that it was cystic fibrosis whose death they yearned for, not that of their sick brothers and sisters.”
The “Death” of this debilitating, inherited illness, either by effective treatment or prevention, is the agenda of the center, which cares for one in every five of Israel’s CF sufferers—120 people in all. Its pediatric pulmonologists, gastroenterologists, endocrinologists, nutritionists, nurses, dietitians, physiotherapists, social workers, psychologists, clinical pharmacists and pulmonary-function technicians all work together. And in addition to disease management, the center has had what looks like a breakthrough in CF treatment that has reached Stage 3 clinical trials.
“Administering a certain antibiotic in the form of nose drops seems to reverse the mutation in the DNA that results in the disease,” says Dr. Eitan Kerem, head of Hadassah’s pediatrics department at Mount Scopus and its Cystic Fibrosis Center.
When CF was first described in the 1940s, average survival was up to a year. Until recently, few children with the disease could expect to live long enough to complete elementary school. But median life expectancy is now 37, both because of advances in managing the disease and integrated multidisciplinary care. In Dr. Kerem’s words, the aim of Hadassah’s CF center is “to enable our patients to become grandparents.”
Dr. Kerem’s interest in CF began when he trained at the Hospital for Sick Children in Toronto, in the late 1980s. “It attracted me from the start,” he says. “Although it’s a chronic disease that can lead to early death, so much can be done to improve both the quality and length of life.”
Cystic fibrosis (also called mucoviscoidosis or mucoviscidosis) is the most common genetic disorder in the Western world, with a particular prevalence among Ashkenazic Jews. Around one in 5,000 people is affected in the general population, and one in 2,500 to 3,000 among Ashkenazim. Passed on when both parents transmit the defective gene located on chromosome 7, cystic fibrosis affects the functioning of the mucus (exocrine) glands. Instead of producing the normal watery mucus that moistens the linings of vital organs and prevents infection, CF patients produce mucus that is thick and sticky. In the respiratory system, it clogs the lungs and leads to life-threatening lung infections. In the gastrointestinal system, it obstructs the pancreas, preventing natural enzymes from breaking down and absorbing food. And in the male reproductive system, it blocks the vas deferens, impeding passage of sperm.
“Disability is progressive and unrelenting,” says Dr. Kerem. “Some patients wheeze and cough persistently…. Some suffer digestive problems, become malnourished and grow poorly, despite a good appetite. Many men will be infertile. With chlorides [salt] sweated out in quantity, the blood-mineral balance is upset, leading to heat-crisis episodes.”
Until recently, treating cf was limited to minimizing its symptoms, avoiding its complications and preventing its progression in a draining daily battle. The coordinated medical care provided at Hadassah is accompanied by education and counseling for struggling patients and their families. Parents and siblings attend support groups that give them coping tools for their fatigue, guilt and sadness.
Hadassah’s emphasis, however, is enabling its CF patients to live as normally as possible. While they come to the center to have blood-glucose levels and pulmonary and pancreatic function checked, much of their care is at home, where they have inhalation machines, monitoring equipment, enteral feeding pumps, intravenous antibiotics and mucus-thinning medications. Patients and families are taught how to aerate laboring lungs and clear them of mucus, strengthen muscles to improve breathing and increase heart- lung resistance so as to minimize the demand for oxygen. Calorie-rich menus are custom-designed for each patient.
These labor-intensive responses to CF, assembled over five decades, have lengthened and improved the lives of its victims. Researchers, however, are hopeful they will soon be relegated to the medical scrapheap. Their hopes lie in correcting the gene whose miscues wreak so much damage.
The CFTR (cystic fibrosis transmembrane conductance regulator) gene, whose mutation causes CF, was first cloned in 1989 by an international research team. One of its members was Dr. Kerem’s wife, Batsheva, a professor of genetics and scientific director of the National Center for Genomic Technology at the Hebrew University of Jerusalem’s Alexander Silberman Institute of Life Sciences. Since returning to Israel in 1990, the two Dr. Kerems have continued their research collaboration in CF.
One of our first projects after we got back was determining the incidence of CF in Israel,” says Dr. Eitan Kerem. “We found that it differs in different ethnic Jewish communities.” The two published their work in an academic paper that is referred to in genetic clinics around the world.
More unexpected still was their discovery that, while the CFTR gene is involved in the disease in every ethnic group, it mutates differently in each. That is, Ashkenazic, Yemenite, Iraqi Jews and other Jewish groups have their own specific mutation. In fact, more than 1,500 mutations in one gene have been identified.
These findings, along with studies worldwide, have enabled a five-category classification system for the genetic mutations that cause not only cystic fibrosis but other protein-linked disorders as well—among them Duchenne’s muscular dystrophy, Hurler syndrome and certain hemophilias and cancers.
Class 1, explains Dr. Kerem, is absence of the essential CFTR protein and is the most common form of CF among Jews. In Class 2—the most common form among non-Jews—there is a defect in processing the protein. The Class 3 mutation is faulty activation of the protein. Classes 4 and 5, which produce a milder form of the disease, are, respectively, reduced functioning and reduced quantity of the protein.
The Kerems and their teams are now investigating why different mutations cause the disease to be expressed in these different ways and degrees of severity. “We believe that when we understand the mechanisms of the different mutations, we’ll be able to develop very specific therapies that will correct the faulty mechanism,” says Dr. Eitan Kerem.
Their main focus is developing a therapy for the form of CF that they see most—Class 1, in which the protein that guides essential chloride in and out of the body’s cells is missing.
“The flawed gene issues a premature command to stop producing the protein, so the flaw is known as the ‘stop’ mutation,” says Dr. Kerem. “Israel, with its high incidence of CF, is the obvious place to study this, and our studies have borne fruit. Eight years ago, we showed that gentamicin, an antibiotic commonly used to treat eye infections, has the remarkable ability to correct the ‘stop’ mutation.”
In their Phase 1 clinical trial, Dr. Kerem and his colleague Dr. Michael Wilschanski, head of pediatric gastroenterology at Hadassah, created gentamicin nose drops for 19 patients.
“We used the nose as a living laboratory,” says Dr. Wilschanski. “After administering two drops three times a day for 14 days, the missing protein appeared in cells lining the nasal tissues…. [The gentamicin] had overwritten the premature ‘stop’ command, enabling continued synthesis of the protein.”
The team had shown for the first time ever that gentamicin corrects the genetic flaw, allowing cells to release chloride ions and water and create healthy mucus that washes the interior of the nose. The next stage was to get gentamicin to the clogged mucus membranes inside the body in the hope that cells in the lungs and gastrointestinal system would normalize in the same way. But this was more complex.
“Gentamicin is extremely toxic, and administering it to the lungs and stomach as we had the nose wasn’t appropriate,” says Dr. Kerem.
At this point, united states- based PTC Therapeutics came on board. “They’d read about our work with gentamicin in the New England Journal of Medicine,” says Dr. Wilschanski. “They were excited about it, because they’d discovered a molecule that has the same effect as gentamicin, without its toxicity.”
The molecule, made into a liquid called PTC124, began clinical trials at Hadassah and four United States hospitals in 2006. “Twenty-four patients took part at Hadassah, swallowing PTC124 three times a day,” says Dr. Wilschanski. “Some weeks into the trial, the mother of one, an 18-year-old boy, told us it was the first time in 18 years she’d not been woken at night by her son’s coughing.”
The next stage is determining appropriate dosage and administration of the medication in a Phase 3 clinical trial in which Hadassah will play a leading role. The hoped-for outcome: eliminating CF with a daily pill. The impact of that outcome, says Dr. Kerem, will be incalculable for the 70,000 children and adults worldwide who struggle to live with CF.
“These people perform some kind of mechanical airway clearance up to four times a day, take multivitamin and pancreatic enzyme supplement capsules with every meal and regularly swallow or inhale mucus-thinning medications, antibiotics, antiinflammatories and bronchodilators,” he says. “And because CF is genetic, there is often more than one family member who is affected. At Hadassah, we treat a family in which 7 of their 10 children have the disease.
“Against this background, you can understand why our research, with its hope of a simple and effective treatment, is so imperative.”