An interdisciplinary team of Weizmann Institute scientists has solved the 3-D structure of an enzyme involved in Gaucher's disease, a genetic illness that mainly affects Ashkenazi Jews. The study, published in EMBO Reports, may lead to the design of effective new therapies.
Gaucher's disease is characterized by swelling and enlargement of the spleen and liver and disruption in the function of these organs; in rare cases, it may also affect the brain. It is caused by the accumulation of a fatty substance, or lipid, called glucosylceramide. Accumulation occurs due to a defect in the enzyme charged with breaking down this lipid and regulating its amount.
Today thousands of Gaucher's patients are treated by injections of this enzyme, in an approach called enzyme replacement therapy, or ERT. The annual cost of the therapy is approximately $100,000 to $300,000 per patient. More affordable alternatives, such as the ones that may emerge from the Weizmann Institute study, are urgently needed.
The Institute team included Prof. Tony Futerman of the Biological Chemistry Department, Prof. Joel Sussman of the Structural Biology Department and Prof. Israel Silman of the Neurobiology Department, as well as Dr. Michal Harel, Lilly Toker and graduate student Hay Dvir.The solved enzyme structure may help in the design of a more effective enzyme that would improve today's ERT. It may also make possible the design of small molecules that will supplement the damaged enzyme in the patient's body, thereby restoring its normal functioning.
Prof. Futerman's research was supported by the Estate of Ernst and Anni Deutsch-Promotor Stiftung, Switzerland; the Paul Godfrey Foundation; the Buddy Taub Foundation; the Sir Siegmund Warburg's Weizmann Trust; and the Estate of Louis Uger, Canada. He is the incumbent of the Joseph Meyerhoff Professorial Chair of Biochemistry.
Prof. Silman's research was supported by the Nella and Leon Benoziyo Center for Neurosciences; the Charles A. Dana Foundation; the Carl and Micaela Einhorn-Dominic Brain Research Institute; and the Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly. He is the incumbent of the Bernstein-Mason Professorial Chair of Neurochemistry
Prof. Sussman's research was supported by the Charles A. Dana Foundation; the Jean and Jula Goldwurm Memorial Foundation; Mr. Yossi Hollander, Israel; the Helen & Milton A. Kimmelman Center for Biomolecular Structure & Assembly; the Joseph and Ceil Mazer Center for Structural Biology; the late Sally Schnitzer; and the Kalman & Ida Wolens Foundation. He is the incumbent of the Morton and Gladys Pickman Chair in Structural Biology.
The research utilized infrastructure provided by the Kekst Family Center for Medical Genetics.
Thanks to a diagnostic imaging technique that should soon find its way to medical establishments, many patients will be spared the pain and risk of biopsies. The technique, which detects breast and prostate cancer, has recently received FDA clearance. Slated for use as early as next year, it will enable doctors to distinguish between malignant tumors and benign lumps by scanning instead of cutting.
Called 3TP (Three Time Point), the technique makes use of existing MRI machinery and a dye-like material (called a "contrast agent") that is injected near the examination site. The site is scanned by MRI three times over a period of several minutes, once before the contrast agent is injected and twice after. The software developed for the method then creates a colored image of the breast or prostate area. A preponderance of red in the image indicates malignancy, while mainly blue and green are signs of a benign growth.
The procedure was developed by Prof. Hadassa Degani of the Institute's Biological Regulation Department. Because 3TP is non-invasive and is based on existing MRI technology that has long been approved, the FDA clearing process was shorter than usual. Clearance is now being sought in Canada and Europe.
Prof. Degani's research was supported by the M.D. Moross Institute for Cancer Research; Sir David Alliance, CBE, UK; Mr. and Mrs. Lon Morton, Calabasas, CA; Mrs. Jackie Gee, Ms. Livia Meyer and Mr. Harry Woolf, UK; Ms. Lynne Mochon and Ms. Edith Degani, NY, USA; the Washington Square Health Foundation; the Willner Family Center for Vascular Biology; and the Estate of Mrs. Ilse Katz, Switzerland. She is the incumbent of the Fred and Andrea Fallek Professorial Chair in Breast Cancer Research.
(l-r) Profs. Israel Silman and Joel Sussman. Molecular maps
A team of Weizmann scientists has gained new insight into a recently approved Alzheimer’s drug called rivastigmine (currently sold as Exelon (TM)), revealing its molecular mechanism.
“The results were surprising,” says Prof. Joel Sussman of the Structural Biology Department. “They show that we can safely treat Alzheimer’s disease with much lower quantities of rivastigmine, thus minimizing adverse effects.”
Rivastigmine, like other Alzheimer’s drugs, works by blocking the action of an enzyme involved in Alzheimer’s disease called acetylcholinesterase (AChE). The scientists – Sussman, Prof. Israel Silman of the Neurobiology Department and Ph.D. student Pazit Bar-On – took complex “snapshots” of rivastigmine bound to AChE.
They then built a molecular map showing the spatial arrangement of all the atoms of AChE and rivastigmine. Using this map, they found that after binding to AChE the rivastigmine molecule breaks in two and moves some of AChE’s atoms, making it difficult for AChE to return to an active state. It thus prolongs the drug’s effect.
Prof. Israel Silman is the incumbent of the Bernstein-Mason Professorial Chair of Neurochemistry. His research is supported by the Nella and Leon Benoziyo Center for Neurosciences; the Charles A. Dana Foundation; the Carl and Micaela Einhorn-Dominic Brain Research Institute; and the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly.
Prof. Joel Sussman is the incumbent of the Morton and Gladys Pickman Chair in Structural Biology. His research is supported by the Charles A. Dana Foundation; the Jean and Jula Goldwurm Memorial Foundation; the Helen and Milton A. Kimmelman Center for Biomolecular Structure and Assembly; the Joseph and Ceil Mazer Center for Structural Biology; and the late Sally Schnitzer.
From left to right: Prof. Carlos Gitler, Rivka Bracha, Prof. David Mirelman and Yael Nuchamowitz. Silencing amoebas
When the Spaniards conquered Mexico in the early 16th century, they were met with an unexpected form of resistance: life-threatening dysentery, which they called "Montezuma's revenge" (Montezuma being the exalted leader of the Aztecs at that time). Tourists traveling to developing countries sometimes go through the same experience.
Today we know that one of the main causes of this disease is an amoeba found in sewage-contaminated drinking water and poorly sanitized food. Amoeba-caused disease claims the lives of thousands yearly and afflicts millions more, mainly in impoverished communities.
Unfortunately, the means to fight amoebic disease remain very limited. Because affected populations usually reside in poor countries pharmaceutical companies do not have sufficient economic incentive to invest in developing new therapies. Now a Weizmann team has succeeded in engineering an amoeba that could become the basis for a pioneering vaccine against amoebic disease.
Kiss of Death
Amoebas are parasites that settle in the victim's intestine, where they reproduce and attack mucosal cells in the intestines' linings. In the early 1980s Profs. Carlos Gitler and David Mirelman of the Weizmann Institute's Biological Chemistry Department received a joint research grant from the Rockefeller Foundation to study dysentery-causing amoebas. Mirelman focused on lectins, the proteins that enable amoebas to attach themselves to intestinal cells. Gitler, who had immigrated to Israel from Mexico where he personally witnessed amoeba-related suffering, discovered that amoebas kill human cells by injecting a small protein into their membranes. Gitler called this protein an amoebapore; the killing phenomenon was coined "the amoeba kiss of death." Gitler hoped to produce antibodies that could be used against the amoebapore. However, the anti-bodies proved ineffective because they couldn't reach the amoebapore, which passed directly from the amoebas into the intestinal cells without being exposed.
Some 15 years later, technological advances encouraged Mirelman to make an attempt to study the amoebapore's role in the development of disease. Mirelman and team members Rivka Bracha and Yael Nuchamowitz isolated the gene encoding the amoebapore, made a copy of the gene and reversed the orientation of its components (called nucleotides). They then reintroduced the reversed gene (called "anti-sense") into the amoeba, creating an organism that carries both the original ("sense") amoebapore gene and the antisense gene. When the original amoebapore gene starts getting expressed, the anti-sense gene does the same. The resulting two molecules (called messenger RNAs) fit together perfectly, clinging to each other like two sides of a zipper. As a result, neither of the messenger RNA molecules is available for producing the amoebapore protein.
Garlic vs. Amoebas
Using this technique the scientists managed to block some 60% of amoebapore production in the amoebas. The engineered amoebas were much less aggressive than their original counterparts. Yet the scientists went further: In follow-up research they managed to completely block the gene that encodes the lethal protein, in effect developing a new breed of "silenced" amoebas incapable of making amoebapore and therefore much less harmful to human cells.
Now the scientists are trying to see whether the silenced amoebas can be used as a vaccine against aggressive amoebas (similar to the way weakened viruses or bacteria are used as vaccines). If successful, this first vaccination of its kind will open the way to ending the suffering of millions affected by the amoeba parasite.
Prof. David Mirelman is the incumbent of the Besen-Brender Chair of Microbiology and Parasitology. His research is supported by the Y. Leon Benoziyo Institute for Molecular Medicine; Erica A. Drake, Scarsdale, NY; Robert Drake, the Netherlands; Mr. and Mrs. Henry Meyer, Wakefield, RI; the M.D. Moross Institute for Cancer Research; and Claire Reich, Forest Hills, NY.
While attending a conference in China around ten years ago, Mirelman asked local Chinese doctors what they prescribed to patients suffering from intestinal diseases. They told him of an ancient remedy that has been used for almost five thousand years, consisting of an alcohol extract made from freshly crushed garlic cloves. They even jotted down the precise recipe. Surprised to hear that this extract cured patients from the infecting microorganisms without ill effects, Mirelman decided to investigate it. Upon returning to the Weizmann Institute, he prepared the solution and found that a specific molecule, allicin, which is found in fresh garlic extracts, kills amoebas by inactivating some of their crucial enzymes. Though the same molecule can affect enzymes in human cells, they, unlike their amoebic counterparts, are able to reactivate these enzymes. The key to reactivating them lies in a substance called glutathione, which exists in mammalian cells but not in amoebas and most other microorganisms. Efforts to develop therapies for amoebic disease based on these findings are currently under way.
Prof. Mirelman on the Great Wall of China. Strategies - old and new
Left to right: Ph.D. student Benny Dekel and Prof. Yair Reisner. Timing is everything
More than 50,000 people in the United States alone are on the waiting list for kidney transplants. The wait can last years – and steadily claim victims along the way.
A landmark study recently reported in Nature Medicine now offers hope of a future solution. Prof. Yair Reisner of the Weizmann Institute of Science has succeeded in growing miniature human kidneys in mice, using human stem cells. His team has also produced pig kidneys in mice, using the same technique. The kidneys were fully functional.
Reisner and Ph.D. student Benny Dekel of the Weizmann Institute’s Immunology Department, with Prof. Justen Passwell, who heads the pediatric department at Tel Aviv’s Sheba Medical Center, transplanted human and pig kidney precursor cells (stem cells destined to become kidney cells) into mice. Both the human and pig tissue grew into perfect mouse-size kidneys. The miniature kidneys were functional, producing urine. In addition, the risk of rejection – a common phenomenon in current transplantation procedures – was greatly reduced, since blood supply within the kidney was provided by host rather than donor blood vessels.
“The findings suggest that one day it might be possible to grow a healthy kidney in a human by transplanting human or pig fetal tissue into the patient,” says Reisner.
Window of opportunity
To date, the key obstacle to transplanting embryonic stem cells from one kind of animal into another has been that of timing: Cells that were too old suffered substantial immune rejection, while cells that were too young were found to develop into disorganized tissue that included non-kidney structures, such as bone, cartilage and muscle.
The Institute team succeeded in pinpointing the ideal time during embryonic development at which stem cells have the best chance of forming well-functioning kidneys with a minimal risk of rejection: 7- to 8-week-old human tissue and 4-week-old porcine tissue were found to offer the optimal window of opportunity for transplantation. Within this time range the tissue lacks certain cells that the body recognizes as foreign.
To determine whether the immune system would reject human and pig kidneys grown in mice, the scientists grew the kidneys in mice that lack an immune system. They then restored the animals’ immunity by injecting human immune cells called lymphocytes. Their findings were encouraging: As long as the kidney stem cells were transplanted at the right stage, the lymphocytes did not attack the new pig or human kidneys. Rejection rates in normal (immune-functioning) mice were also reduced compared to those caused by older stem cells. “If all goes well, we hope to begin human trials within a few years,” says Reisner.
The challenge of stem cell therapy
The current accomplishment of growing functional kidneys in mice using human stem cells marks yet another milestone in the career of Prof. Yair Reisner, whose prize-winning stem cell research has spanned more than 20 years.
Stem cells in bone marrow (the sponge-like tissue found in the center of certain bones) are the precursors of red and white blood cells. They play a crucial role in transplant therapies aimed at saving the lives of people with acute leukemia and other blood disorders.
The strategy, however, depends on finding a compatible donor. Patients lacking a suitable donor among their siblings have to search the general population, and many fail to find one, even though donor registries – which include more than 8 million volunteers – have been established worldwide.
Collaborating with a team led by Prof. Massimo Martelli of Italy’s Perugia University, Reisner has made it possible to transplant even partially matched stem cells in leukemia patients. Nearly 400 patients throughout Europe have been treated using the new approach, yielding significant success rates, as reported in the New England Journal of Medicine, Science and other leading journals. Reisner and Martelli recently received the Daniele Chianelli Prize for their work.
The first mismatched transplant using the Reisner-Martelli approach was attempted in 1993, in a 20-year-old factory worker from Italy who had no matched donor in his family. As there was no time to search for an unrelated donor, physicians intended to perform an autologous transplant (using the patient’s own stem cells), but before the transplant was ready, the patient’s disease had progressed to a critical stage. At the family’s request, the Perugia team attempted their new approach, using the patient’s father as a partially matching donor.
Following a successful recovery, the patient was able to resume his normal lifestyle and return to his job at the factory, where he still works today.
Prof. Yair Reisner is the incumbent of the Henry H. Drake Professorial Chair in Immunology. His research is supported by Richard M. Beleson, San Francisco, CA; Renee Companez, Australia; the Concern Foundation; the Crown Endowment Fund for Immuno-logical Research; Erica A. Drake, Scarsdale, NY; Robert Drake, the Netherlands; the Ligue Nationale Francaise Contre le Cancer; the M.D. Moross Institute for Cancer Research; the Gabrielle Rich Leukemia Research Foundation; Rowland Schaefer, Pembroke Pines, FL; and the Union Bank of Switzerland-Optimus Foundation.
Detecting an intruder, the body sounds an alarm, alerting fighter cells to the site. How this intricate feat is pulled off - with immune cells coursing through the body's circulatory system knowing exactly which "exit"to take into nearby affected tissues - has mystified scientists for years (see previous page). Now researchers at the Weizmann Institute of Science have discovered that equally important lessons may be gleaned from cells that perform the exact opposite - running away from trouble like the plague.
Dr. Idit Shachar of the Institute's Immunology Department and her Ph.D. student Liat Flaishon found that young B cells (a class of immune cells known as lymphocytes) veer away from distressed areas, in marked contrast to their adult counterparts. Shachar wondered what mechanism was protecting them from getting caught on the front lines at a young age, when they were ill-equipped to survive. And more importantly, she thought, could this mechanism possibly be used to remove adult immune cells from the battlefield when, as occasionally happens, the immune response goes awry, attacking the body itself?
Inappropriate immune responses occur when the body's call for help turns out to be a false alarm and, in the absence of an invader the mobilized lymphocytes end up attacking the host, or when lymphocytes overreact at the height of an attack. This kind of attack could cause problems ranging from mild inflammation to life-threatening diseases, including asthma, multiple sclerosis, and diabetes.
Shachar's team found that in contrast to adult lymphocytes, which have long been known to secrete high levels of a substance called interferon gamma, young B-cells secrete only minute levels of this substance. Small quantities of interferon gamma short-circuit the young B-cells' ability to reach the site of trouble.
After discerning this substance's exact mode of action, Shachar and her group, including Dr. Ian Topilski and Flaishon (who is also a physician), set out to determine whether interferon gamma could indeed be used to inhibit the combative action of adult immune cells. To do so, they created an asthma model using mice. Asthma, a very common inflammatory disease, is a particularly dangerous immunological overreaction, in which lymphocytes swarm the lymph nodes of the lungs, thickening the bronchial walls and making breathing difficult or impossible.
The results of the initial experiments were encouraging: Minute doses of interferon gamma dramatically reduced bronchial inflammation in asthmatic mice. Shachar now plans to administer interferon gamma to mice during late-stage asthmatic episodes to determine whether it can alleviate an acute crisis. Ultimately, she intends to apply the treatment to asthmatic humans - an experiment for which Ichilov Hospital has recently given approval. Concurrently, she is running experiments using interferon gamma to suppress other types of inflammation and has achieved heartening preliminary results for colitis.
illustration: Young B cells run from trouble
Dr. Shachar's research is supported by the Harry and Jeanette Weinberg Fund for the Molecular Genetics of Cancer; the Philip M. Klutznick Fund, Chicago, IL; the Weizmann Institute of Science - Yale Exchange Program; Mr. Mauricio Gerson, Mexico; and Mr. Udi Angel, Israel. She is the incumbent of the Trudy and Alvin Levine Career Development Chair.
"You don't assign him murder cases. You just turn him loose," claimed promos for Dirty Harry, a popular film of the 1970s starring Clint Eastwood. This daredevil cop-hero may now have a cellular counterpart fighting disease - a special type of cell that helps counter transplant rejection. When about to be attacked by another cell, this cell "draws" first and promptly destroys the attacker. Scientists refer to this cellular feat as "veto" activity because the cell has veto power over its own destruction.
Weizmann Institute researchers suggest that veto cells may have the ability to improve bone marrow transplantation, now performed mainly in leukemia patients, and make such treatment worthwhile for patients with non-lethal blood disorders. (In a bone marrow transplantation, stem cells from the donor's bone marrow are transplanted into that of the patient.) In the future, veto cells may also facilitate the transplantation of such organs as the heart, liver, and kidneys.
Until recently, doctors believed that for stem cell transplantations to succeed, a full match between the donor and recipient was necessary. Patients having no donor among their siblings must search the general population, but for roughly half of them a donor is found too late or not at all.
Over the past decade, Prof. Yair Reisner of the Weizmann Institute's Immunology Department, together with Prof. Massimo Martelli of Italy's Perugia University, has conducted research that has enabled transplants of partially matched stem cells in leukemia patients. Using this method, donor and recipient need be matched for only three of six immunological markers. Such a match is always present between parents and children, and there is a 75% chance of finding it among siblings. If the search includes the extended family, more than 95% of patients can find a donor.
Hundreds of patients throughout Europe have been treated using this approach, yielding significant success rates, according to the New England Journal of Medicine and other publications. These results indicate that mismatched transplants can be as effective as those in which donor and recipient are fully matched. Phase 1 studies are currently under way in major centers in the United States, and the European Bone Marrow Transplantation Society has recently launched a prospective study in more than 30 medical centers throughout Europe.
A key element of Reisner's approach is the use of extremely large doses of donor marrow, which literally overwhelm the recipient's rejection mechanism. The donor is treated with hormone injections that release a large number of stem cells from the bone marrow into the bloodstream, from where they are selectively removed. But how does bombarding the patient with a megadose of donor stem cells prevent transplant rejection? "Strength in numbers sounds simple enough," says Reisner. "Yet what are the underlying mechanisms?"
In two new studies, Reisner and his team members - Dr. Esti Bachar-Lustig, Rita Krauthgamer, Judith Gan, and doctoral students Shlomit Reich-Zeliger and Hilit Gur - provided insights into this riddle. They showed that the key to success lies in stem cells endowed with potent veto activity, which are capable of protecting themselves against rejection by the body's immune system. When these cells sense that they are about to be attacked, they impose their veto by selectively killing off the attacking immune cells without harming the rest of the patient's immune system. The success of megadoses would thus result from veto cells being present in larger numbers.
It may be possible to harness this veto mechanism to make bone marrow transplantation less demanding on the body. Currently, to reduce the risk of transplant rejection, the patient's immune system is suppressed using large doses of drugs and radiation that in themselves can be lethal. Reisner has shown that the number of veto cells can be increased 80-fold, and he proposes using larger numbers of such cells in a transplant. This approach should allow doctors to use lower drug radiation levels prior to transplantation, which in turn should reduce the side effects and the risk of mortality associated with the procedure.
While bone marrow transplantation is still considered too risky for patients with non-lethal diseases such as thalassemia and sickle-cell anemia, Reisner's gentler transplantation procedure may be appropriate for these diseases. The veto mechanism could improve the success rate of organ transplants as well: Veto stem cells could be injected at the time of the transplant to serve as "bodyguards" that prevent rejection of the transplanted organ.
Prof. Reisner's research is supported by the Gabrielle Rich Leukemia Research Foundation, Switzerland; the M.D. Moross Institute for Cancer Research; the UBS Optimus Foundation, Switzerland; Mrs. Erica Drake, New York; the Ligue Nationale Francaise Contre Le Cancer, France; Mrs. Renee Companez, Australia; and Stanley A. Lewis, New York, NY. He holds the Henry H. Drake Professorial Chair in Immunology.
Prof. Tsvee Lapidot and Ph.D. student Isabelle Petit. Raising anchor
To obtain healthy stem cells for transplantation - either from a healthy donor or from the patient himself before or during chemotherapy - these cells must be encouraged to exit the marrow into the bloodstream (in other words, they must be "mobilized"). Looking for the mobilization signal, Prof. Tsvee Lapidot of the Institute's Immunology Department and Ph.D. student Isabelle Petit studied the cascade of events in the bone marrow leading to mobilization.
The scientists learned that stem cells in the marrow are freed into the bloodstream via a key protein called SDF-1. SDF-1 had previously been found by this and other research teams worldwide to anchor stem cells inside the marrow by activating adhesion molecules (molecules that serve as "glue"). Lapidot and Petit found that for stem cell mobilization to take place, SDF-1 must be degraded, and they uncovered an underlying "anchors aweigh"mechanism.
The findings, published in Nature Immunology, may lead to the improved collection of stem cells for clinical transplantations. Key elements of the opposite process - the migration of cells into the marrow - were elucidated by Lapidot and his colleagues in an earlier study. The scientists managed to dramatically increase the proportion of stem cells capable of migrating to the marrow, a factor critical to the success of transplantation. Both studies were made possible by a unique experimental system developed by Lapidot's team.
Prof. Lapidot's research is supported by the M.D. Moross Institute for Cancer Research; the Gabrielle Rich Center for Transplantation Biology Research; the Levine Institute of Applied Science; Mr. Clifton Robbins, New York, NY; the Naftali Foundation, Israel; the Concern Foundation, Beverly Hills, CA; Ms. Nora Peisner, Huntington, MI; and Ms. Rhoda Goldstein, Nanuet, NY.
A team of researchers led by Prof. Irun Cohen of the Weizmann Institute of Science has developed a vaccine that halts the progression of Type I (juvenile or insulin-dependent) diabetes. The vaccine functions by blocking the destruction of insulin-secreting pancreatic cells.
Diabetes is a chronic disease associated with elevated blood sugar levels, in which the body does not produce or improperly uses insulin - a hormone needed to convert sugar, starches and other foods into energy. Recent data show that between 120 and 140 million people suffer from diabetes worldwide. Type I diabetes usually results from an autoimmune disorder in which the immune system mistakenly attacks the body's own insulin-producing pancreatic cells, reducing and ultimately eliminating all insulin production. All Type I diabetes patients eventually must receive insulin injections to compensate for their loss of natural insulin production.
For the past several years researchers at the Weizmann Institute's Department of Immunology led by Cohen have been studying the mechanism by which the immune system destroys the insulin-producing pancreatic cells. Working with mice, the scientists discovered that a particular protein called HSP60 was closely linked to this destructive process.
The protein acts like an antigen, prompting the immune cells to attack. Further investigation by Cohen, Dr. Dana Elias (first a graduate student and then a postdoctoral fellow at the Institute), and other students and colleagues revealed that injecting sick mice with p277, a small peptide fragment of the HSP60 protein, shut down the immune response, preventing the progression of Type I diabetes. This led Peptor Ltd., a biopharmaceutical company based in Rehovot, Israel, to develop the experimental drug DiaPep277, designed to prevent or treat Type I diabetes.
A combined clinical study performed recently by researchers at Hadassah-Hebrew University Medical School, Peptor Ltd., and Cohen proved that DiaPep277 is successful in arresting the progression of Type I diabetes in newly diagnosed patients. The research findings were published in the Lancet.
The study involved 35 patients newly diagnosed with Type I diabetes. Eighteen patients received injections of DiaPep277 - at the beginning of the study, after one month, and after six months; 17 patients received three injections of an inert substance (a placebo). Patients in the treatment group (those receiving DiaPep277) showed a delay or even a cessation in the attack by the immune system upon their pancreatic insulin-producing cells. These results were evident in the level of the body's own insulin production and a decreased need for insulin injections. The researchers were able to trace the mechanism of this improvement to changes in the patients' immune lymphocytes called T-cells. In contrast, patients receiving the placebo showed a significant decline in their natural insulin production and a persistent rise in the need for insulin injections. No significant side effects as a result of injecting DiaPep277 were found.
'The idea of using p277 stemmed from the discovery that the immune system has different options to choose from in responding to an antigen,' says Cohen. 'It can act to destroy the antigen or alternatively protect it from being destroyed. In the latter case it protects the antigen, thereby indirectly preventing damage to the pancreatic cells. The peptide essentially acts to 'reeducate' the immune cells, switching off their destructive activity.'
The scientists participating in this study are: Prof. Itamar Raz and Dr. Muriel Metzger of Hadassah-Hebrew University Medical School; Dr. Dana Elias (now VP R&D at Peptor Ltd.); and Drs. Ann Avron and Merana Tamir, also of Peptor Ltd.
Prevention rather than replacement
Back in 1920 Dr. Federick Banting and Charles Best of the University of Toronto made a discovery that would change the course of medical history. They had succeeded in obtaining a pancreatic extract which proved to have potent anti-diabetic characteristics when tested on dogs. Within two years their team would isolate and purify the extract's key ingredient, a hormone known as insulin, and the first human trial would begin, extending the life of Leonard Thomson, a fourteen year-old-boy who lay dying in hospital, for an additional 13 years.
Today extensive research efforts have yielded dramatically improved high-quality insulin as well as better delivery methods. Nevertheless insulin is not a cure, it merely helps to maintain blood sugar levels in check. A cure would be to stop the autoimmune destruction, sparing the insulin-producing beta cells. In contrast to the replacement therapy offered by insulin, the vaccine currently in development by Prof. Cohen's team has been shown to prevent the destruction of pancreatic cells.
Prof. Cohen holds the Helen and Morris Mauerberger Professorial Chair in Immunology. His research is supported by the Robert Koch Minerva Center for Research in Autoimmune Disease, the Yeshaya Horowitz Association, and Mr. and Mrs. Samuel T. Cohen, Illinois.
Glaucoma is the leading cause of blindness in adults, affecting one percent of the adult population. Weizmann Institute scientists have now succeeded in putting the brakes on progressive eyesight loss in experimental animals afflicted with a glaucoma-like disease. Their study, reported in Proceedings of the National Academy of Sciences, U.S.A., suggests that Copaxone, a drug developed at the Weizmann Institute to treat multiple sclerosis, may also stop, or at least slow down, eyesight loss in people with chronic glaucoma.
The majority of patients with chronic glaucoma have increased pressure inside the eye due to defective drainage of the transparent fluid that bathes the eye and nourishes its outer cells. This intraocular pressure (IOP) damages the optic nerve, causing it to degenerate and often leading to blindness. (Operating much like an electric cable, the optic nerve is a bundle of more than 1 million nerve fibers, which carry the images we see to the brain.)
For many years, the search for improved glaucoma therapies focused on correcting the eye's drainage system to reduce IOP. Eventually however, it became apparent that reducing the pressure was not enough to arrest glaucoma, as it did not halt optic nerve degeneration. Scientists concluded that a crucial factor was somehow being overlooked, and they set out in search of this missing link.
Approximately five years ago, Prof. Michal Schwartz of the Weizmann Institute's Neurobiology Department proposed a new concept to account for the continued optic nerve degeneration occurring in spite of successful treatments to reduce eye pressure. Schwartz suggested that while the initial damage to the optic nerve is indeed caused by increased eye pressure, secondary factors triggered by the initial damage contribute to the nerve's ongoing degeneration. When the nerve is damaged, chemicals that normally play an important role in neuronal cell maintenance increase to a toxic level. One of these chemicals is the neurotransmitter glutamate, which spills from damaged nerve cells and adversely affects healthy neighboring cells.
In line with this concept, Schwartz developed an original strategy for tackling the problem. To protect the nerve from the harmful chemicals in the body, she recruited the immune system (although its well-known role is actually to defend the body from external "invaders"). This approach raised eyebrows at first, mainly because it involved cells that, when activated, usually cause one of the autoimmune diseases, in which the body mistakenly attacks itself - such as juvenile diabetes and multiple sclerosis. The concept of using these "enemy" cells to heal the body seemed uncanny.
Schwartz - who has also developed an immune-based therapy for spinal cord injuries now undergoing clinical trials - has demonstrated that contrary to accepted wisdom, autoimmunity can play a beneficial role in the body. A series of studies in her lab showed that in rats, immunization with protein fragments from myelin, the sheath enveloping nerves, reduces the extent of degeneration after acute injury of the rat optic nerve or spinal cord. However, the clinical use of such protein fragments, or peptides, for immunization is fraught with risk because some of these peptides cause the immune system to attack nerve fibers, leading to multiple sclerosis. Since humans vary greatly in their genetic make-up, it is difficult to establish which of the peptides would be risky in a specific patient.
Looking for a safe alternative to these peptides to treat glaucoma, Schwartz and her group, in collaboration with Profs. Irun Cohen and Michael Sela of the Weizmann Institute's Immunology Department, turned to Copaxone, a synthetic compound which reacts with immune cells that recognize and respond to self proteins. Copaxone was developed at the Institute by Dr. Dvora Teitelbaum and Profs. Ruth Arnon and Michael Sela as a drug for multiple sclerosis. The team demonstrated that in glaucoma, immunization with Copaxone protects the damaged optic nerve from neuronal degeneration. And the most recent study by Schwartz, Dr. Eti Yoles, and graduate students Jonathan Kipnis and Hadas Schori may explain why. The Weizmann team found that immunization with Copaxone shields the nerve from the toxic effects of neurotransmitter glutamate. These studies were corroborated in another series of experiments, conducted together with scientists at the U.S. based company Allergan Inc. (who developed the rat model that simulates chronic glaucoma). In rats immunized with a single injection of Copaxone, only about 4 percent of the nerve cells in the glaucoma-affected eye died, compared with 28 percent in the control group. These collective findings strongly suggest that Copaxone immunization is a potential therapy for glaucoma. Following these findings, trials in human patients with glaucoma are expected to begin shortly. Scientists hope that the trials will be facilitated by the fact that the U.S. Food and Drug Administration has already approved the use of Copaxone.
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Deciphering Gaucher's Disease