Finding parents for orphan diseases

Rare Diseases Day was marked on February 29. Of some 5,000 of them, about 400 can be treated.

Only one individual in the world has ever been diagnosed with an inscrutable fatal genetic disorder known as ribose-5-phosphate isomerase deficiency, making him the quintessential sufferer of an “orphan disease” so rare that no one bothers to make a drug to treat it.
But most “orphan” – rare – diseases have hundreds, thousands, tens of thousands or even more sufferers around the world.
As pharmaceutical companies prefer to develop “blockbuster” medications that will be needed by many millions of people for the rest of their lives, they tend not to invest in finding effective treatments or cures for orphan diseases. In addition, physicians and researchers are generally reluctant to study disorders that affect only a handful of people.
Aware of the problem, the US Congress passed in 1983 the Rare Diseases Orphan Product Development Act that gives financial incentives to drug companies that develop medications for orphan diseases and reduce research requirements for them to be accepted by the Food and Drug Administration.
The Rare Diseases Act of 2002 established the statutory authorization for the US Office of Rare Diseases as a federal entity able to recommend a national research agenda, coordinate research and provide educational activities for researchers.
The first Rare Disease Day was held in Europe and Canada – observed on February 29 to symbolize rarity, that month having an extra day only every four years.
The Knesset has never passed a law to give benefits to Israeli research institutes and drug companies for developing drugs for orphan diseases. But on February 29, last week, a conference on rare disorders was held at Sheba Medical Center at Tel Hashomer, and Health Minister MK Ya’acov Litzman attended to give his greetings.
In some 80 percent of cases, rare diseases are passed on by defective genes and are thus chronic disorders; most of the 5,000 known orphan diseases kill victims in childhood.
About a third of children with orphan diseases will die before reaching their fifth birthday.
The rest of the rare disorders are apparently caused by viruses or allergies or due to degenerative of proliferative cells (that wildly produce more cells). The European Commission on Public Health defines orphan diseases as “life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them.”
TO MARK the event and raise awareness about rare diseases and their impact on patients’ lives, The Jerusalem Post went to the Fuld Family Department of Medical Genetics at Jerusalem’s Shaare Zedek Medical Center to interview Prof. Gheona Altarescu, director of the its Pre-Implantation Genetic Diagnosis (PGD) Unit, one of the country’s and the world’s leading experts in identifying, treating and avoiding the birth of embryos with Gaucher’s, Fabry and other rare genetic disorders.
PGD is a reproductive technology used with an in-vitro fertilization cycle for diagnosis of genetic disease, removing one cell within the embryo’s first five days to ensure it is normal before implanting it.
“We have eight technicians and two staffers with MDs and PhDs. I am the genetics adviser, and Prof. Ephrat Levy-Lahad is director of the department.”
Altarescu, a physician and geneticist who was born in Romania and made aliya at the age of 24 after completing medical school, is somewhat embarrassed when asked about her first name, which means “genius.” How do parents know that their newborn baby, an only child in Gheona’s case, is going to be a genius? She laughs.
“My father was a chemical engineer and a Hebrew teacher, so he and my mother chose it to remember my grandmother Golda. My maternal grandfather was the chief rabbi of Romania for many years. As an only daughter, I brought an end to 23 generations of sons who descended from the Ba’al Shem- Tov (Rabbi Yisrael ben Eliezer, the 18th-century founder of Hassidic Judaism).” Many members of the family were murdered by the Nazis in the Holocaust. After receiving her MD, she went to the US National Institutes of Health to study genetics. She was accepted by Shaare Zedek’s internal medicine department but wanted a field that combined gynecology, obstetrics and genetics, so her current specialty was perfect for her.
“THERE IS no official ratio for calling a disorder an orphan disease,” said Altarescu. Some say one in 100,000 or 70,000. In the US, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically “any disease or condition that affects fewer than 200,000 people in the United States,” or about one in 1,500 people. This definition is essentially like that of the Orphan Drug Act of 1983. In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients or about one in 2,500 people in that country. In Israel, it is usually defined as one in 1,000.
Fabry, resulting from a deficiency of the enzyme alpha galactosidase A, was named for one of its discoverers, Johannes Fabry (1860 to 1930). It is a “tricky” disease because it can affect adults and not only children and can cause a variety of medical problems, each handled by different specialists – neurologists, cardiologists, dermatologists, kidney doctors, pain experts and others.
So it is sometimes misdiagnosed. Doctors often don’t ask about systemic symptoms irrelevant to their specialty, and the patient may have forgotten that he had symptoms years ago, such as pain, that disappeared, said Altarescu. Fabry patients have a somewhat shortened life expectancy.
Fabry is a rare genetic lysosomal storage disease, inherited in an X-linked manner, so females who have two X chromosomes (and one may be normal) may overcome the sick gene, while males have only one X chromosome (and one Y), so they tend to be at higher risk for it. Men typically suffer from severe symptoms, women can range from being asymptomatic to having severe symptoms. The first enzyme-replacement treatment for Fabry’s disease, called Fabrazyme, was approved by the FDA in 2003. It is not a cure, but it can improve metabolism and partially prevent disease progression, as well as potentially reverse some symptoms.
The pharmaceutical company Shire manufactures agalsidase alpha (which has a somewhat different molecular structure) under the brand name Replagal, made from human cells, which is given by infusion into a vein every two weeks for 40 minutes each time.
Sometimes, a Fabry patient is allergic to a drug that can help him. Shaare Zedek’s team performed “desensitization” for such a patient, giving a little of the drug each time until he was able to get the infusion without harm. “When Fabry is diagnosed,” explained Altarescu, “it is often too late, as it becomes irreversible. Thus we have to work hard on awareness of Fabry among doctors and the public. There are only about 40 patients here, among them Arabs, Iraqi Jews and Ashkenazi Jews.”
SHAARE ZEDEK also has the national center for Gaucher’s disease, which was the first orphan disease for which enzyme replacement was given. The Gaucher Clinic director is Prof. Ari Zimran. One in 17 Ashkenazi Jews has Gaucher’s; it is much less common among Sephardi Jews. Genzyme’s Ceredase was developed to treat Gaucher patients, and later it was genetically engineered as Cerezyme.
Protalix, an Israeli company, also produces a Gaucher drug, made from carrots, and the firm was later bought by Pfizer.
A Korean company also offers a drug for it. Patients can get infusions at home from technicians or nurses, but a new company is working on the development of a pill as well, Altarescu said. The center also diagnoses and treats Hunter syndrome, the X-linked recessive lysosomal storage disease caused by a deficient (or absent) enzyme, and others.
IT IS fortunate that patients with any of the orphan diseases for which there is treatment can get them from their public health fund as part of the national basket of health services, even though only about 10% of rare diseases have a drug relevant to patients that extend life and prevent advancement of the disease.
“Research here into orphan diseases is very advanced because of the large variety of ethnic and other groups, including those that ‘inbreed’ [first cousins marry] such as Arabs, Beduin and hassidic ultra-Orthodox Jews.”
Altarescu and colleagues at Shaare Zedek, the Hebrew University and in Germany just published an article in The Journal of Clinical Investigation about non-invasive prenatal testing of blood to find abnormal numbers of chromosomes in circulating blood to prevent the birth of severely defective fetuses.
THERE IS an amazingly large representation of women in genetics here, said Altarescu.
“Women are especially thorough, with the ability to look through a great deal of medical literature. Female doctors can get more attached to the case and have more understanding of the sensitivities of pregnant women carrying a fetus with malformation or having to go through IVF and PGD,” she added.
It isn’t true that women tend to go into the specialty because they have an 8-to-5 schedule on weekdays. “Fewer men go into genetics because there is no demand for more-profitable private medical services in the afternoons and evenings that are usually sought out by male doctors who want to earn more,” she added.
“We set up our PGD lab in 2005. When I was younger, I remember remaining in the lab until 2 or 3 a.m. on PGD procedures.
There are emergencies in fetuses too,” she says, sitting behind a wall covered with photos of some of the normal babies whose birth she and her colleagues made possible by using PGD. “We have done this for 500 babies; we can’t fit all of them on the wall.”
The genetics institute, located on the fifth floor, has received millions of dollars in donations from real-estate philanthropist Rabbi David Fuld, who with his wife gave money to establish it and perform PGD. After PGD to produce two healthy babies was included in the basket for health services, Fuld set up a fund to cover the cost of the procedure for couples who want a third baby and beyond.
“We are the largest PGD unit in Israel and one of the largest in Europe,” said Altarescu.
“We provide PGD services for Sheba, Tel Aviv Sourasky, Rabin-Beilinson Campus, Soroka, Assaf Harofe and Wolfson Medical Centers and also the private Herzliya Medical Center.
“As many of the diseases are very rare, I refer patients with some of them to other medical centers here. Hadassah University Medical Center in Jerusalem and Rambam Medical Center in Haifa, for example, have a lot of experience with metabolic diseases such as Pompe disease. We also have ongoing contacts with colleagues abroad who have special expertise in specific rare diseases,” said the geneticist.
If she could have a meeting with Litzman, she would suggest to him the passage of a law, modeled after that in the US, to encourage the development of orphan drugs.
“I asked the Health Ministry’s chief scientist’s office for a grant for Fabry research, but I was turned down. The office has very little money, a few millions of shekels, at its disposal. This small country has four or five centers specializing in PGD while there are three or four in all of England, but we need more manpower, as we see an exponential increase in the number of women who turn to us to have a healthy baby.”