Three decades ago, neurologists had almost nothing to offer patients suffering from multiple sclerosis (MS), the potentially disabling autoimmune disease of the central nervous system. Yet today, there are nine different approved medications – a significant number of them developed by Israelis – that can try to halt acute attacks.
With MS, as if a wire were stripped of its plastic coating, the immune system attacks the protective sheath (myelin) that covers nerve fibers and causes communication problems between the brain and the rest the body. Eventually, the disease can cause the nerves themselves to degenerate or become permanently damaged.
Symptoms of MS vary widely and depend on how much damage has been suffered and which nerves are affected. Some patients with severe MS may lose the ability to walk, while others may experience long periods of remission without any new symptoms.
Early MS symptoms include weakness, tingling, numbness, blurred vision, muscle stiffness and urinary problems. There is no MS cure, but various medications – by infection, infusion or oral pills – can help speed recovery from acute attacks, modify the course of the disease and manage symptoms.
The nine approved treatments are injectible interferon beta-1a, interferon beta-1b, glatiramer acetate (Copaxone), mitoxantrone, natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio, which is taken as oral pills), dimethyl fumarate and alemtuzumab (Lemtrada, taken by infusion). All of the available treatments are available in Israel’s basket of health services.
MS takes several forms, with new symptoms either occurring in isolated attacks (relapsing remitting) or building up over time (progressive). Between attacks, symptoms may disappear completely; however, permanent neurological problems often remain, especially as the disease advances.
MS HAS been the focus for 30 years of Prof. Dimitrios Karussis – a senior, Greekborn neuroimmunologist and head of the Center for Multiple Sclerosis at Hadassah University Medical Center in Jerusalem’s Ein Kerem.
As chairman of the Israel Neuroimmunological Society, he also orchestrated the four-day biennial conference of the International Society of Neuroimmunology held at the end of September at the Jerusalem International Convention Center.
Some 700 physicians and experts with doctoral degrees in the field of immunology and neurology from 26 countries attended the 17th International Congress on Neuroimmunology. “The who’s who of the field were all here. We had lectures by 100 invited speakers,” Karussis told The Jerusalem Post during an interview at the conference. “For more than 20 years, that had not been a meeting in Israel of experts in the field,” he added. The first day was an “immunology school” with 400 PhDs and doctoral students from around the world.”
As a non-Jewish exchange student from Salonika in 1986, Karussis spent a month at Tel Aviv Sourasky Medical Center and then moved on to Hadassah. Two years later he and his wife Orania (also a physician) were back for good, after he won a scholarship for research. Now their 18-year-old son is about to be inducted into the Israel Defense Forces.
Although his MS research has suffered cuts and delays in the recent past to the Hadassah Medical Organization’s financial problems, he said that the Hadassah Women’s Zionist Organization has given his projects high priority.
From the beginning of his career, Karussis has been interest in inflammation, a complicated biological response of the body’s tissues to harmful stimuli, such as damaged cells, pathogens, damaged cells or irritants.
But it is not only negative. “Inflammation can also be very positive, as it is a protective response involving immune cells, blood vessels, and molecular mediators.”
The function of inflammation is to eliminate the initial cause of cell injury, clean up dead cells and tissues damaged from the original event and the inflammatory process and to start tissue repair.
Nearly a quarter of a century ago, Karussis began using adult stem cells experimentally as a treatment for amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), a rapidly progressive, invariably fatal disease that attacks the nerve cells that control muscle action we can control such as those in the face, arms and legs.
“ALS is a model of degenerative disease and is supposed not to be inflammatory, but now it seems as if it involves inflammation as well. Inflammation is involved in Alzheimer’s and Parkinson’s diseases, for example. But this process not only causes damage. Inflammation can be beneficial because to have recovery and regeneration, you need some kind of inflammation, with microphages to clean up debris from damaged cells. Without inflammation, for example, you can’t recover from influenza.”
There are around 700 Israelis with ALS and some 5,000 with MS. There is no gender difference in ALS, but there are twice as many women with MS. In addition, the geographical distribution is not equal; there are more patients the farther one gets from the equator, thus there are more in Northern Europe (one patient per 500 residents) and North America and less in Israel (one per 1,000).
Karussis notes that pregnancy is “good for MS patients,” as the hormones seem to stop or prevent attacks, but after the women give birth, there are relapses. All the same, pregnancy seems to be beneficial in the long run. Women who have many children are better off than those who have none or only a few.
Half of MS patients become progressive after 15 years, while in others, the attacks can remain intermittent. In 10% of patients, they already begin as progressive cases. The disease does not directly cause death, but in some cases it can reduce life expectancy by five or eight years due to complications. The earlier you begin treatment, the greater the likelihood that it will help and protect the abilities that patients still have.
KARUSSIS IS collaborating with Brain- Storm Cell Therapeutics, based in Petah Tikva, which is commercializing a Tel Aviv University technique for treating ALS by growing and adapting adult stem cells. The process involves taking bone marrow from ALS patients and culturing it under sterile conditions in his lab. A month later, the small number of cells multiply themselves to many millions and can be used to try to restore lost motor neurons.
Copaxone is a drug, developed at Rehovot’s Weizmann Institute of Science by Prof.
Michael Sela, Prof. Ruth Arnon and the late Dr. Dvora Teitelbaum and marketed by Teva Pharmaceuticals. Over 20 years after being introduced, the immunomodulator drug is still widely used here and around the world to treat MS. A random polymer of four amino acids found in myelin basic protein named glutamic acid, has been approved by the US Food and Drug Administration for reducing the frequency of relapses.
New medications such as Aubagio and Lemtrada compete with older treatments but there are plenty of patients (some 2.5 million around the world) who can benefit, said the Hadassah neuroimmunologist, and in any case, the drugs – with a variety of side effects – should each be personally suited to the condition and stage of the illness. “All have advantages and disadvantages. There are side effects and safety issues for each of them. Gilenya, for example, might cause irregular heartbeat. Other MS drugs can cause gastrointestinal problems. Some drugs are given only if two others previously were ineffective, and others are given as firstline drugs.”
“It’s hard to bring together the companies making the older and the newer drugs to do studies together involving the taking a pair of drugs. “They involve different pathways and molecules, so it could be may be problematic.
Karussis is deep in clinical research at Hadassah giving up to 48 patients from around the world who have been diagnosed with primary progressive injections of their own processed stem cells into the fluid in their spines. “There is an internal mechanism for myelination, but it is only partially effective, so we want to enhance this mechanism,” said Karussis.
“This can modulate inflammation, and the stem cells can provide an external source of myelin. We started six months ago, and 38 have already been involved.
There is space for only 10 more suitable patients. It is double blinded, so only half get the actual treatment, but we crossover and then give the stem cells to the other half,” he said.
As the stem cells are at an early stage when they can turn into myelin, they might be able to re-coat damaged nerves.
He is hopeful that the treatment could make a significant difference in the lives of MS patients everywhere.
“Over the next five or 10 years, there will be an additional revolution for patients with MS and other neurodegenerative diseases,” he speculates.
ALSO AT the neuroimmunology conference were Portugese-born Isabel Firmino, the head of global MS Medical Affairs at Sanofi Genzyme, a huge pharmaceutical company based in Boston. The company makes two new drugs, Lemtrada (which is being taken by thousands around the world, including Israelis) and Aubagio (given to 300 so far). Lemtrada, said Firmino, has been shown to be very effective in stopping relapses.
“I came to the company 11 years ago,” she said. “What attracted me was that Sanofi Genzyme is very patient oriented, with a focus on their needs.”
Genzyme, which the French company Sanofi bought in 2011, is well known in Israel because of its development of Ceredase/ Cerezyme for effective treatment of the “Jewish genetic disease” Gaucher.
Other genetic diseases it has worked on are Fabry and Pompe diseases, which are also more common in Jews.
Firmino studied medicine in Lisbon and practiced a number of years as a school health physician, after which she joined the pharmaceutical industry. Sanofi Genzyme has invested not only in MS treatments but also in vaccines and now, also in atopic dermatitis and cancer.
She noted that Lemtrada is given by infusion for just five consecutive days during the first year and three times in the second.
Follow up has found that they do not need more but continues to be effective.
“There are many MS patients who still benefit from interferons and from Copaxone. We want all patients to be under control. But others who are not should get access to what helps them,” she added.
“It’s amazing how Israel is a center of such much promising MS research.”
“We collaborate from the early phases of development,” said Michael Eliav, the general manager of Genzyme Israel, who is based in Netanya. “Genzyme has been working in Israel for more than 20 years due to the commitment to treating Gaucher. The Israel center for the disease is run by Prof. Ari Zimran at Jerusalem’s Shaare Zedek Medical Center.”
“Our company always regarded Israel as a target for conducting research because of the high quality of doctors and researchers here. Israel, with its diverse ethnic population is a great place to study genetics,” Eliav explained.
He added that it was unfortunate Israel lacks an “orphan drug law” unlike the US and many other countries. Such legislation gives bonuses to companies that research and produce treatments for “orphan diseases” that affect only a relatively small number of patients. “It is crucial to have such a law here, as there are no criteria in Israel for what an orphan disease is and no bonuses for companies that devote their resources to finding treatments.”