New hope for patients with cystic fibrosis
Israeli scientists take extraordinary measures to conquer CF
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PrintThe recent film “Extraordinary Measures” tells the real-life tale of a family with two children who are suffering from a fatal genetic disorder. Their father takes drastic steps to encourage and support the work of a brilliant scientist, whose insight leads to a miracle drug that saves the lives of the children. The CF story may have a similar path to a happy ending — with the work of some extraordinary Israeli physicians and researchers leading to a new approach to cure CF.
The CFTR protein is the source of all problems in cystic fibrosis. CFTR stands for cystic fibrosis transmembrane conductance regulator. Its normal function is to move salts across cell membranes throughout the body — a process that is essential to the proper functioning of the lungs, kidneys, pancreas, and other organs, as well as the normal growth and development of the vas deferens, a structure that transports sperm in men.
Israeli scientist and physician Eitan Kerem has spent more than two decades studying CFTR and cystic fibrosis from a genetic as well as a clinical perspective. Dr. Kerem’s research, in collaboration with many other Israeli researchers as well as other scientists worldwide, has helped reveal the genetic underpinnings of CF, as well as the most effective ways to treat patients and alleviate symptoms of the lethal disease.
 | Dr. Eitan Kerem |
Kerem’s research career started in the early 1980s, with his first CF papers appearing in 1989. At that point, he and his colleagues were already intrigued by the genetic and clinical aspects of CF. He began to publish studies of specific mutations 20 years ago, with the identification of Delta F508 as a major mutation in the Ashkenazi Jewish community. Kerem co-authored a paper in 1992 on W1282X, a nonsense mutation in the Ashkenazi Jewish population. This was an early exploration into the possibility of treating different mutations using different approaches.
Kerem, along with colleagues at Shaare Zedek Medical Center, and later at Hadassah Medical Center, also pursued various approaches to treating the lung infections and other complications in CF patients. His publication list includes a 1992 paper on “Undescended testis and absence of vas deferens,” describing male infertility issues of CF, as well as an intriguing article, written in Hebrew, on “CF as a model of ethical issues: Abortion of fetuses carrying a disease with survival to adulthood.” He was also involved with research on “nasal potential difference measurements,” a measure of secretions in the nose; that research has led to a reliable test to diagnose CF.
Kerem was named director of Pediatric Pulmonary Medicine at Shaare Zedek Hospital in 1996. In the 1990s, he and his co-workers published numerous articles on a variety of mutations associated with CF. In 2000, Kerem was co-author of a paper that described the use of the antibiotic gentamicin to bypass a nonsense mutation, and restore normal gene activity. Gentamicin turned out to be toxic in concentrations needed to overcome the mutation. Although it was not practical for treatment of CF patients, the gentamicin research led to the development of other pharmaceuticals that could accomplish the same goal — the restoration of normal protein production in patients with nonsense mutations — with much lower risks of toxicity.
In 2002 Kerem was appointed head of the Department of Pediatrics at Hadassah Medical Center, where he founded the Center for Chronic Diseases in Children. He and his colleagues published a landmark paper in 2005 in the renowned British journal The Lancet, reporting on the “induction of CFTR function in patients with cystic fibrosis: Mutation-specific therapy.” This report suggested that genetic mutations could be treated and overcome with drug therapy. The Lancet published an account of the Phase II clinical trials of PTC124, now known as Ataluren, in a paper authored by 14 researchers, including senior authors Kerem and Michael Wilschanski of Hadassah Hebrew University Hospital in Jerusalem, scientists from PTC Therapeutics in South Plainfield, N.J., as well as researchers from the Hebrew University Department of Genetics and three other Israeli hospitals. That paper serves as one of the cornerstones in the research for an effective drug to help CF patients overcome the basic genetic defect of the disease.
Kerem is by no means a one-man show; many of his publications include names of scientists that he has collaborated with many times in the past 20 years, including his wife, Dr. Batsheva Kerem. But his remarkable record of more than 140 published papers is testimony to a life dedicated to curing this very challenging disease. The state of the research now appears to be highly promising and may prove to have generated a long-awaited drug that will extend the lives, and improve the quality of life, of many CF patients.
Hadassah Hebrew University Hospital now has a Cystic Fibrosis Center at the Mount Scopus campus in Jerusalem that offers services for patients with cystic fibrosis. Kerem is its director. The multidisciplinary approach includes pediatric and adult medical care by specialists such as pulmonologists and gastroenterologists, as well as nutritional counseling, psychological services, and support groups for families. It provides screening and genetic testing services and physiotherapy, and its research faculty and staff continue to pursue studies to improve the quality of life of CF patients, as well as to identify and address the basis of the disease.
“We started the phase III Ataluren study in Hadassah three months ago, and enrolled, so far, close to 20 patients,” reports Kerem.
Information on the CF Center at Hadassah can be found at http://www.hadassah.org.il/English.
More on: New hope for patients with cystic fibrosis
Clinical trials of Ataluren
To be considered for the clinical study on the new drug Ataluren, originally called PTC124, CF patients “must know their genetic mutation,” said Teaneck resident Dr. Jay Barth, executive director of clinical development at PTC Therapeutics, Inc., the South Plainfield-based company that is beginning Phase III trials for the new drug. Barth, a Teaneck resident, explained that “many patients already know their mutation. If not, they have to have genetic testing.” Patients who carry at least one copy of a nonsense mutation (see below) may qualify. Also, patients must be at least six years of age, and have lung functioning within a certain range.
Cystic fibrosis can be caused by many different forms of mutations in the CFTR gene. The CFTR gene makes a protein that normally handles the movement of salt across membranes and the secretion of fluids and mucous. Since fluid management and mucous play important roles in many critical organs, CF can affect the lungs, liver, pancreas, reproductive structures, and sweat glands.
Lisa and Steven Yourman and their two teenage children have all the trappings of the typical suburban Jewish family. A ketubah (Jewish marriage contract) and family portraits are displayed prominently on the wall of their split level home, their cat roams around the books, electronics, and other possessions of a busy family life, and a basketball hoop and four cars occupy their driveway. But their Fair Lawn home also has signs of their remarkable challenge: the medical equipment and cartons of medical supplies necessary to care for Sarah and Jeffrey, both of whom have cystic fibrosis.
Cystic fibrosis (CF) is a genetic disease affecting about 30,000 people in the United States. It is more prevalent in Caucasians. The incidence among Ashkenazi Jews is similar to that for Tay-Sachs: About one in 29 Ashkenazi Jews is a carrier. Carriers have no symptoms, but when two carriers have a child there is a one in four chance that the child will have CF.
