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.

In the cells, genetic instructions normally direct the ribosomes — cellular protein factories — how to assemble proteins. Some mutations change genes so that a dysfunctional protein is made. Nonsense mutations are stop signals that are located in the middle of a gene; they cause the production of protein to be interrupted prematurely, so a shortened protein is made. Ataluren is a chemical that can help ribosomes ignore the stop signal and complete the protein. When the normal protein is made, normal functioning throughout the body can be restored. If this approach works, Ataluren could essentially cure the disease in patients with the nonsense mutation.

Dr. Jay Barth

“About 10 percent of CF mutations are due to nonsense mutations,” said Barth. However, within Ashkenazi Jewish CF patients, up to 60 percent of mutations are nonsense mutations.

A three-month Phase II study, led by Drs. Eitan Kerem and Michael Wilschanski and their colleagues, was conducted at Hadassah Medical Center in 2008. The results of the study, published in The Lancet, suggested that many patients had improved salt transport in their tissues. “Hadassah was always a leader in CF research, in particular because of the high percentage of nonsense mutations in the population there,” said Barth. “They are one of the sites in the Phase III study.”

“There are numerous sites in the U.S., Europe, and Israel that are actively recruiting for the Phase III study,” said Barth. Children’s Hospital in Pittsburgh is taking applications and Saint Vincent’s Hospital in Manhattan is planning to participate, although it has not started recruitment yet. Other sites are planned for Westchester and New Jersey, but they have not been finalized.

During the trial, patients will take the drug three times a day in powder form, mixed with water, juice, or milk. The drug is absorbed through the digestive system, enters the blood stream, and goes everywhere in the body, targeting the production of protein by ribosomes affected by nonsense mutations.

The double-blind randomized trial will involve dividing the patients into two groups — one of which will receive the drug and the other a placebo for 48 weeks. Barth explained that after the initial study there will be an “open label extension study where all patients who choose to may continue for another year on the drug.” If proven to be effective in correcting cystic fibrosis due to nonsense mutation, the drug would have to be taken for the rest of the patient’s life. Research has shown that the drug is generally well tolerated with few side effects and very high patient compliance (up to 99 percent of patients continue to take it).

Barth explained that numerous other diseases are caused by nonsense mutations in other genes, and they might also be helped by Ataluren. There have been clinical trials of Ataluren for Duchenne muscular dystrophy caused by nonsense mutations, and there are also studies under way for hemophilia caused by nonsense mutations. Barth said that an estimated 15 percent of all patients with 7,000 rare genetic disorders have nonsense mutations, and many of those patients could be helped by this novel therapeutic drug.

“This gives hope of treating a disease that, until now, there has been nothing to treat the underlying cause,” said Barth. He noted that there are other types of drugs being developed that may be useful for other types of mutations. “Science is advancing and hopefully there will be several different treatments for CF,” Barth said.

Information on PTC Therapeutics and Ataluren clinical trials can be found at http://www.ptcbio.com. For more information, call Diane Goetz, patient advocate, at (866) 282-5873. Information on clinical trials can be found at www.clinicaltrials.gov.

The 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.

Sarah and Jeffrey Yourman don’t let their disease keep them from an active life.

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.

CF is a lifelong illness with no cure. It affects many critical organs, including the lungs, liver, and pancreas. Just a few decades ago a CF patient’s life expectancy was in the teens, but now, because of antibiotics and other advances in treatment of symptoms, many CF patients live active lives into their 50s.

Lisa and Steven Yourman have hope that the prognosis for their two children will be even better, as a new drug that treats the underlying defect is being tested and may soon become available. Over the years there have been many potential therapies offering hope that did not pan out, but the new drug, Ataluren, works in an entirely different way, explained Lisa Yourman. “There were other drugs I never got excited about. There was an IV [intravenous] medication that, when given in very high doses, corrected the defect, but there were serious adverse reactions. But this one is different. The drug is 11 years in the making,” she said.

“Everyone carries two copies of the gene for the sodium channel protein. The two versions could be the same or different,” said Yourman. The Yourman children have among the most common mutations: Delta F508 and G542X. It is the G542X mutation that gives them hope, as it is a so-called “nonsense mutation.” Normal genes provide instructions to guide the production of all the proteins that control the functions of the body. When a nonsense mutation occurs, the mutated gene contains an error that blocks the production of a complete protein. A CF nonsense mutation is an error in the genetic instructions that interrupts production of a key protein needed for transport in many organs. The partial protein that is made does not work properly and leads to serious complications in mucous secretion and production of other fluids. The new drug Ataluren may be able to reverse the defect caused by a nonsense mutation such as G542X mutation (see sidebar).

“The drug has been extensively tested at Hadassah Hospital in Israel,” said Yourman. “The drug is in clinical trials. Now it is being tested around the world.” Lisa recalled her late mother-in-law, Janet Yourman, who was very active in Fair Lawn’s Hadassah chapter, raising money for Hadassah Hospital for almost 50 years. Lisa believes that work of Janet Yourman and others like her on behalf of Hadassah may have helped lead to the development of this drug.

The Yourmans will be applying for Sarah and Jeffrey to participate in Phase III trials at Children’s Hospital in Pittsburgh, where trials are scheduled to begin shortly. It is a 48-week double-blind randomized trial, which means that half the patients get the treatment and half a placebo, an inert medication. “The worst that can happen is that you can waste a year,” said Lisa, referring to the possibility that her children might be assigned to the placebo group. After the trial, the patients who received the placebo are eligible to take the drug.

“We are so excited. I hope they both qualify,” she said.

Life in a CF family

Lisa Yourman demonstrates the preparation of antibiotics for Sarah’s IV. MIRYAM WAHRMAN

For Lisa Yourman, taking care of two children with CF involved learning how to administer medications, advocate for medical services, negotiate complex health insurance issues, and schedule daily therapy sessions, all while providing opportunities for Sarah and Jeffrey to have normal childhood activities. The treatments for CF symptoms have improved dramatically, allowing the children to live remarkably normal lives despite the fact that the regimen needed to maintain their health is daunting. Yourman works as an advocate to help other parents deal with CF and has even lobbied in Trenton on health-care issues.

Yourman brims with pride over her children’s accomplishments. “I have two kids with chronic disease with them every single day of their lives, and they are very successful academically,” she said.

Sarah, 19, is a sophomore at Kean University. The petite and perky teen is studying for a bachelor of fine arts degree in theater design and technology and would like to work in theater lighting design. Sarah also suffers from CF-induced diabetes and she has done public speaking as a diabetes advocate. She was on the cover of “Diabetes Positive” and received the Michael Brennan courage award in 2009 from the CF community.

When she is at college, Sarah gets up two hours before class to perform her treatments, which involve using a mechanical vest that dislodges the mucous in her lungs. Before bed she takes a handful of pills, including antibiotics and medications to thin the mucous.

“I’m not afraid to share that I have CF and diabetes,” said Sarah. “There are four of us students who are really close and work together [on projects]. There is an 8-foot ladder to reach the equipment in their 12-foot ceilings. It’s dubbed the Sarah Yourman ladder,” she said with a smile. “When I first got there I would not get on the ladder, but I got over the fear of ladders. We also have a cherry picker in the department, for the main theater, and I went up in it,” she said.

Growing up, Sarah was a competitive free-style skier, a sport that involves jumps and aerial stunts. Now she focuses on downhill skiing and has recently taken up snowboarding. Throughout the winter, Sarah and her father work as ski coaches at Wyndham Ski Resort. “I usually go skiing every weekend from December until mid-March,” she said. “This year I have so much going on that I just go whenever I can.”

Jeffrey Yourman demonstrates the mechanical vest. MIRYAM WAHRMAN

She still laments the season she missed when she was 16 and had scoliosis surgery. “I have two titanium rods and 16 screws in my back,” she said, adding with a smile that this coincides with her birthday, which is Feb. 16 (2/16).

When Sarah is home, she gets chest physical therapy, which Jeffrey still gets 365 days a year. “The kids get beaten on every day,” said their mother. A physical therapist drums the chest and back with cupped hands to dislodge excess mucous and relieve breathing. The treatment, which may be needed several times a day, lasts about 45 minutes. For Sarah, being home also frequently involves intravenous antibiotic treatment to counteract infections she may have picked up at school.

Since many CF children have growth issues, both Sarah and Jeffrey were prescribed growth hormone. “Jeffrey, who started at an earlier age, is still on it,” said Yourman. “His predicted height was 5 feet, and he is now 5 feet 7 1/2 inches.”

Jeffrey and Sarah have both participated in camps and trips sponsored by Chai Lifeline, Camp Simcha, and a new organization called Kids of Courage. Those organizations provide mechanisms for Jewish children with serious medical needs to enjoy camping and travel experiences. “In March 2009 Jeffrey took a fully paid trip to L.A,” said Yourman. “The camp takes care of medicine, therapy, etc. They are phenomenal in every way in dealing with medical issues.”

Although Jeffrey’s approach to dealing with CF is “don’t think about it,” he displayed remarkable patience and willingness to discuss his experiences. A sophomore in high school who just turned 17, Jeffrey is excited about getting his driver’s license. He loves to play basketball and is a Lakers fan. For Jeffrey, the Make-A-Wish Foundation sponsored their family for a Hawaiian cruise last year. His favorite part of the trip was driving a dune buggy.

The Yourman children do not have activities together with other CF teens. “Because of cross-infection, CF kids are not allowed to hang around together,” said Yourman. “Jeffrey doesn’t have much contact with other kids who have CF since it presents a risk that they will transmit infections to each other.”

“Whatever your kids want to do, don’t say no,” Yourman advised. “The only time our doctor said ‘no’ was when Sarah wanted to go to EMT school and volunteer on the ambulance,” because of the risk that she would be exposed to infections.

“A normal life is whatever life you lead that brings satisfaction to you and inspiration to others,” Sarah said. “I lived it all my life, so I don’t know how to live it any other way.”

Information on the clinical trials for Ataluren can be found at www.ptcbio.com. Information on CF can be found at the Website of the Cystic Fibrosis Foundation, www.cff.org