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Israeli scientists identify: Genes that affect responses of multiple sclerosis patients to copaxone

Contact: Yivsam Azgad
news@weizmann.ac.il
972-893-43856
Weizmann Institute of Science

A group of Israeli scientists from the Technion – Israel Institute of Technology, the Weizmann Institute of Science and Teva Pharmaceutical Industries have recently identified genes responsible for the positive response of many multiple sclerosis patients to the drug Copaxone®. These findings may contribute to the development of personalized medicine for multiple sclerosis sufferers.

Copaxone® was the first original Israeli drug to be approved by the U.S. Food and Drug Administration (FDA), and is today marketed in over 40 countries worldwide, including the U.S.A., Europe, Australia, Latin America and Israel.

The drug molecule was the fruit of research by Prof. Michael Sela, Prof. Ruth Arnon and Dr. Dvora Teitelbaum of the Weizmann Institute’s Immunology Department. It was developed for the treatment of multiple sclerosis (MS) by Teva, which produces and markets Copaxone® today.

‘Until now, medical treatments for all kinds of diseases have relied on trial and error methods to determine dosage and treatment protocols,’ says Prof. Ariel Miller of the Ruth and Bruce Rappaport Faculty of Medicine at the Technion, and Head of the Multiple Sclerosis and Brain Research Center, Carmel Medical Center, Haifa. ‘But the process of fixing the correct dosage affects the efficacy of the treatment and can lead to complications in some cases.’ In the past few years, it has been shown that many drugs are not equally effective for every patient, and this variability is due, at least in part, to genetic differences. Finding medications and doses to suit the genetic make-up of each individual patient is likely to be more successful and to cause fewer side effects.

The new research, which deals with the genetic components of the response to Copaxone®, was recently published in the journal Pharmacogenetics and Genomics. It represents a significant step toward realizing this medical vision. In the collaborative study, Teva supplied DNA samples from drug-treated patients, and the genetic tests were performed at the Crown Human Genome Center of the Weizmann Institute, headed by Prof. Doron Lancet of the Institute’s Department of Molecular Genetics. The scientists used state-of-the-art equipment – the first of its kind in Israel –which allows for the rapid and accurate scanning of variations in the human genome. The scientists then examined the links between the genetic markers they found and the response of MS patients to Copaxone®. They identified several genes that are tied to a positive response to the drug. ‘We analyzed the DNA sequences in 27 candidate genes from each patient participating in the trial,’ said Lancet, ‘and we identified two genes with a high potential for determining the response to Copaxone®. In the future, it may be possible to use this method to scan the genome of MS sufferers, to predict the response levels in advance, and to optimize the dosage and treatment protocol to suit each patient personally.’

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Also participating in the research were Prof. Jacques Beckmann (formerly at the Weizmann Institute); Drs. Liat Hayardeny and Dan Goldstaub of Teva; and Iris Grossman, a joint research student at the Technion and the Weizmann Institute.

Copaxone® – Interface between Past and Future

In the 1950’s, Prof. Efraim Katzir of the Weizmann Institute of Science, later fourth president of the State of Israel, commenced research on the properties of proteins – the building blocks of all biological systems. This research led to the design of simple synthetic models of proteins, called ‘polyamino acids.’ His research student at the time, Prof. Michael Sela (who later became President of the Weizmann Institute and was the recipient of, among many honors, the Israel Prize), decided to test the influence of these synthetic molecules on the immune system. This research led him to the conclusion that it might be possible to use these synthetic substances to curb symptoms of multiple sclerosis – an autoimmune disease in which the body’s immune system attacks proteins in the fatty layer surrounding nerve fibers, preventing the conductance of electrical signals through them. Sela, together with his student at the time, Prof. Ruth Arnon (recipient of the Israel Prize and past Vice President of the Weizmann Institute and Vice President of the Association of Academies of Sciences in Asia), and Dr. Dvora Teitelbaum, conducted a long series of experiments. These experiments eventually led to the development of Copaxone®, and clinical trials carried out by Teva showed its efficacy in treating MS. At the end of the process, in 1996, Copaxone® became the first original Israeli drug to be approved by the FDA. Today, following ten years of active sales in the U.S. and 40 countries around the world, Copaxone® has made a significant contribution to the Israeli economy.

Prof. Doron Lancet’s research is supported by the Nella and Leon Benoziyo Center for Neurological Diseases; the Crown Human Genome Center; and the Laub Fund for Oncogene Research. Prof. Lancet is the incumbent of the Ralph and Lois Silver Professorial Chair in Human Genomics.

The Weizmann Institute of Science in Rehovot, Israel, is one of the world’s top-ranking multidisciplinary research institutions. Noted for its wide-ranging exploration of the natural and exact sciences, the Institute is home to 2,600 scientists, students, technicians and supporting staff. Institute research efforts include the search for new ways of fighting disease and hunger, examining leading questions in mathematics and computer science, probing the physics of matter and the universe, creating novel materials and developing new strategies for protecting the environment.

Weizmann Institute news releases are posted on the World Wide Web at http://wis-wander.weizmann.ac.il.

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October 10, 2007 Posted by | FMS Global News, Global Health Vision, Global News, MS, Multiple Sclerosis, News, News Israel | 5 Comments

Antibody leads to repair of myelin sheath in lab study of multiple sclerosis and related disorders

Contact: Amelyn Reyes
newsbureau@mayo.edu
507-284-5005
Mayo Clinic

ROCHESTER, Minn. — Mayo Clinic researchers have found that a human antibody administered in a single low dose in laboratory mouse models can repair myelin, the insulating covering of nerves that when damaged can lead to multiple sclerosis and other disorders of the central nervous system.

The study will be presented on Oct. 9 at the American Neurological Association meeting in Washington, D.C.

“The repair of chronic spinal cord injury is seldom modeled in laboratory studies, but it is an important reality for the treatment of humans. The concept of using natural human antibodies to treat disease of this kind has not yet been tested in humans, but these research findings are very promising,” says Moses Rodriguez, M.D., a Mayo Clinic neurologist and the study’s corresponding author. “The findings could eventually lead to new treatments that could limit permanent disability,” states Arthur Warrington, Ph.D., a Mayo Clinic scientist and study author.

Myelin repair normally occurs spontaneously, but in multiple sclerosis and other disorders of the central nervous system, the myelin repair process occurs very slowly or fails altogether. Researchers are trying to determine how to speed up the myelin healing process, which they hope will eventually lead to new treatments for patients.

The antibody, which was genetically engineered from a single cell, binds to myelin and the surface of cells in the brain and spinal cord, then it triggers the cells to begin the repair process called remyelination. This antibody is the first known reagent designed to induce repair by acting within the central nervous system at the damage sites on cells responsible for myelin synthesis.

The study uses laboratory mouse models of chronic progressive multiple sclerosis in humans. The severity of the disease and also success of the treatment were largely defined by how naturally active the mice were, particularly during the night because mice are nocturnal and are especially active at this time. They received a single dose of the antibody. A minimum of 25 mcg/kg was needed to trigger remyelination, which is equivalent to about 2 mg in the average adult, considered a very low dose. The myelin repair plateaued after five weeks in the mice models.

In addition, when combined with daily methylprednisolone, (an immune modulating steroid) the antibody still promotes remyelination in mouse models. This is an important fact because the first multiple sclerosis patients treated with the antibody will have been treated first with methylprednisolone.

As a naturally occurring protein of the immune system, antibodies do not appear to carry any side effects, nor are they toxic — even when administered at 4,000 times the minimal effective dose — though the concept has not yet been tested in humans, the researchers say.

In summary, this antibody:

Promotes remyelination with a single dose as low as 25 mcg/kg in mice models

The remyelination plateaus at five weeks after a single dose

Converts a model of chronic immune mediated demyelination to one that repairs with the speed of a toxin induced model of demyelination

In terms of replicating the findings in humans, the researchers have already produced the antibody through genetic engineering and conducted preliminary toxicology experiments in mice showing that 1,000 times the therapeutic dose is not toxic. The study continues to be explored in animal models and eventually, in clinical trials.

In short, the critical finding is that when combined with methylprednisolone, the antibody still effectively promotes remyelination and does not make the mice worse, Dr. Warrington states.

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About Multiple Sclerosis:

Multiple sclerosis (MS) is a chronic, potentially debilitating disease that affects the central nervous system, which is made up of the brain and spinal cord. Multiple sclerosis is widely believed to be an autoimmune disease, a condition in which the immune system attacks components of the body as if they’re foreign.

Multiple sclerosis affects an estimated 300,000 people in the United States and probably more than 1 million people around the world — including twice as many women as men. Most people experience their first signs or symptoms between ages 20 and 40.

Collaboration and Support

The study was funded by the National Institutes of Health, the National Multiple Sclerosis Society, Multiple Sclerosis Society of Canada, the Hilton Foundation and Mr. and Mrs. Eugene Applebaum.

To obtain the latest news releases from Mayo Clinic, go to http://www.mayoclinic.org/news. MayoClinic.com (www.mayoclinic.com) is available as a resource for your health stories. For more on Mayo Clinic research, go to http://www.mayo.edu.

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October 9, 2007 Posted by | Global Health Vision, Global News, Mayo Clinic, MS, Multiple Sclerosis, News, News USA, Ottawa, RSS Feed, Toronto, UK, Washington DC City Feed | 3 Comments

New gene mutation identified in common type of dementia

ST. PAUL, MN — Researchers have identified a new gene mutation linked to frontotemporal dementia, according to a study published in the July 10, 2007 issue of Neurology®, the medical journal of the American Academy of Neurology.

Frontotemporal dementia, one form of which is known as Pick’s disease, involves progressive shrinking of the areas of the brain that control behavior and language. Symptoms include language problems and personality changes, often with inappropriate social behavior. Unlike Alzheimer’s disease dementia, the disease does not affect memory in the early stages. The genetic form of the disease is rare; most cases occur randomly.

“We are hopeful that this finding will help us better understand how this disease works and eventually help us develop new therapies for the disease,” said study author Amalia Bruni, MD, of the Regional Neurogenetic Centre in Lamezia Terme, Italy.

The researchers discovered a new mutation in the gene named progranulin in an extended family in southern Italy. The genealogy of this family has been reconstructed for 15 generations, going back to the 16th century; 36 family members have had frontotemporal dementia. For this study, DNA tests were conducted on 70 family members, including 13 people with the disease. “This is an important result that we pursued for more than 10 years,” said study co-author Ekaterina Rogaeva, PhD, with the Centre for Research in Neurodegenerative Diseases at the University of Toronto.

The mutation identified in this study is in a gene on chromosome 17. The mutation leads to a loss of progranulin, a protein growth factor that helps brain cells survive. The mutation causes only half of the protein to be produced, because only one copy of the gene is active. Production of too much progranulin has been associated with cancer.

The new gene mutation was found in nine of those family members with the disease and 10 people who are currently too young to have the symptoms of the disease. But four people with the disease did not have the gene mutation. Bruni noted that these four people belong to a branch of the family with the disease in at least three generations. “These results are intriguing, since the family has two genetically distinct diseases that appear almost identical,” said Bruni.

The Italian family had no cases with two copies of the mutated gene. “We would have expected to see cases with two copies of the mutated gene, especially since this family shares much of the same genetic material, as there have been at least five marriages between first cousins over the years,” Bruni said. “It’s possible that loss of both copies of the progranulin gene leads to the death of embryos, and that’s why there were no cases with two copies of the mutated gene.”

“Another intriguing aspect in this Italian family is the variable age at onset, which ranged from 35 to 87 years in the family members who inherited the same mutation. Our future research will try to identify the modifying factors responsible for the severity of the disorder,” said Rogaeva.

Rogaeva says their studies will also try to identify the second gene responsible for dementia in this family.

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The study was supported by grants from the Canadian Institutes of Health Research, Howard Hughes Medical Institute, Canada Foundation for Innovation, Japan-Canada and Canadian Institutes of Health Research Joint Health Research Program, Parkinson Society of Canada, W. Garfield Weston Fellows, Japanese Society for the Promotion of Science, National Institute on Aging Intramural Program, Italian Ministry of Health, and the Calabria Regional Health Department.

The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.

For more information about the American Academy of Neurology, visit http://www.aan.com.

Contacts:

Angela Babb
ababb@aan.com
651-695-2789

Robin Stinnett
rstinnett@aan.com
651-695-2763

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July 10, 2007 Posted by | Alberta, Alzheimers, Baltimore, Barcelona, Bethesda, Calabria Regional Health Department, Calgary, Canadian Institutes of Health Research, Cancer, Chromosome 17, Epilepsy, Genes, Genetic, Genetic Link, Genetics, Global, Global Health Vision, Global News, Howard Hughes Medical Institute, Italy, Japanese Society for the Promotion of Science, Joint Health Research Program, Lamezia Terme, Multiple Sclerosis, Neurodegenerative Diseases, News, News Australia, News Canada, News Israel, News Italy, News Jerusalem, News Switzerland, News UK, News US, News USA, Ottawa, Parkinson Society of Canada, Parkinson's, Pick's Disease, Progranulin, Protein Growth Factor, Research, RSS, RSS Feed, Stroke, The American Academy of Neurology, Toronto, University of Toronto, Virginia, W. Garfield Weston Fellows, WASHINGTON, Washington DC, Washington DC City Feed, World News | Leave a comment

Low vitamin D levels may be common in otherwise healthy children

Many otherwise healthy children and adolescents have low vitamin D levels, which may put them at risk for bone diseases such as rickets. African American children, children above age nine and with low dietary vitamin D intake were the most likely to have low levels of vitamin D in their blood, according to researchers from The Children’s Hospital of Philadelphia.

A study in the current issue of the American Journal of Clinical Nutrition measured blood levels of vitamin D in 382 healthy children between six years and 21 years of age living in the northeastern U.S. Researchers assessed dietary and supplemental vitamin D intake, as well as body mass, and found that more than half of the children had low blood levels of vitamin D. Of the subjects, 55 percent of the children had inadequate vitamin D blood levels and 68 percent overall had low blood levels of the vitamin in the wintertime.

“The best indicator of a person’s vitamin D status is the blood level of a vitamin D compound called 25-hydroxyvitamin D,” said Babette Zemel, Ph.D., a nutritional anthropologist at Children’s Hospital and primary investigator of this study. “Vitamin D deficiency remains an under-recognized problem overall, and is not well studied in children.”

Vitamin D is crucial for musculoskeletal health. The primary dietary source of the vitamin is fortified milk, but the best way to increase vitamin D levels is from exposure to sunshine. Severe deficits in vitamin D may lead to muscle weakness, defective bone mineralization and rickets. In addition to musculoskeletal effects, vitamin D is important for immune function, and low blood levels of the vitamin may contribute to diseases such as hypertension, cancer, multiple sclerosis and type 1 diabetes. Decreased blood levels of vitamin D have also been linked to obesity.

Further study is needed to determine the appropriate blood levels of vitamin D in children, said Dr. Zemel, who added that a review of the current recommendations for vitamin D intake is needed.

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Grants from the National Institutes of Health and several private sources supported this study.

Dr. Zemel’s co-authors were Mary B. Leonard, M.D. and Virginia A. Stallings, M.D., of The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, as well as Francis L. Weng and Justine Shults, also of the University of Pennsylvania School of Medicine.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking third in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents. For more information, visit http://www.chop.edu.

Contact: Joey Marie McCool
McCool@email.chop.edu
267-426-6070
Children’s Hospital of Philadelphia

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July 9, 2007 Posted by | 25-hydroxyvitamin D, Alberta, American Journal of Clinical Nutrition, Baltimore, Barcelona, Bethesda, Bone Diseases, Calgary, Cancer, Childhood Nutrition, Children's Hospital of Philadelphia, Children’s Hospital, Children’s Hospital of Philadelphia, Diabetes, Global, Global Health Vision, Global News, hypertension, Irvine, Japan, Juvenile Diabetes, Medical Journals, Multiple Sclerosis, National Institutes of Health, News, News Australia, News Canada, News Israel, News Jerusalem, News Switzerland, News UK, News US, News USA, NIH, Nutritional Anthropology, Osaka, Pennsylvania, Rickets, Slovakia, Spain, Type 1 Diabetes, University of Pennsylvania School of Medicine, University of Pittsburgh, Virginia, Vitamin D, WASHINGTON, Washington DC, Washington DC City Feed, World News | Leave a comment

Testosterone may help men with multiple sclerosis

Contact: Mark Wheeler
310-794-2265
JAMA and Archives Journals

A small pilot study suggests that testosterone treatment is safe, well tolerated and may reduce symptoms, slow brain degeneration and increase muscle mass in men with relapsing-remitting multiple sclerosis, the most common form of the disease, according to a report in the May issue of Archives of Neurology, one of the JAMA/Archives journals.

Multiple sclerosis is a progressive disease involving the immune and central nervous systems. MS and many other autoimmune diseases (in which the body attacks its own systems or tissues) are less common in men than in women, according to background information in the article. This is especially true during reproductive years. Sex hormones, including testosterone and estrogen, may be responsible for the difference. Testosterone has been shown to protect against an MS–like condition and other autoimmune diseases in animals.

Nancy L. Sicotte, M.D., of the David Geffen School of Medicine at UCLA, Los Angeles, and colleagues conducted a study of testosterone treatment in 10 men with relapsing-remitting MS, characterized by periods of neurologic symptoms (such as numbness or difficulty walking) followed by periods of remission. The men, who had an average age of 46, were enrolled in the study and then entered a six-month pre-treatment phase, during which symptoms were monitored but no therapies were administered. Then, each man applied 10 grams of a gel containing 100 milligrams of testosterone to his upper arms once daily for 12 months.

“One year of treatment with testosterone gel was associated with improvement in cognitive performance and a slowing of brain atrophy [deterioration],” the authors write. During the first nine months of the study—the period of time before the men began taking testosterone, plus the first three months of treatment, before it had time to take effect—brain volume decreased an average of -0.81 percent per year. In the second nine months, this decline slowed by 67 percent to an annual rate of -0.25 percent. “Because the protective effect of testosterone treatment on brain atrophy was observed in the absence of an appreciable anti-inflammatory effect, this protection may not be limited to MS, but may be applicable to those with non-inflammatory neurodegenerative diseases,” including amyotrophic lateral sclerosis or Lou Gehrig’s disease, the authors write.

In addition, lean body mass (muscle mass) increased an average of 1.7 kilograms (about 3.74 pounds) during the treatment phase. Participants did not report any adverse effects, there were no abnormalities in blood tests taken during the trial and the men’s prostate examination results remained stable.

“Overall, in this first trial of testosterone treatment in men with relapsing-remitting MS, the treatment was shown to be safe and well tolerated,” the authors conclude. “In addition, exploratory findings reported herein suggest a possible neuroprotective effect of testosterone treatment in men, which warrants further investigation.”

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(Arch Neurol. 2007;64:683-688. Available pre-embargo to the media at http://www.jamamedia.org.)

Editor’s Note: This study was supported by grants from the National Multiple Sclerosis Society, the General Clinical Research Centers at Harbor-UCLA Medical Center, the Sherak Family Foundation and the Skirball Foundation. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

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May 14, 2007 Posted by | Global, Global Health Vision, Global News, JAMA, Multiple Sclerosis | 4 Comments

Glucosamine-like supplement inhibits multiple sclerosis, type 1 diabetes

A glucosamine-like dietary supplement has been found to suppress the damaging autoimmune response seen in multiple sclerosis and type-1 diabetes mellitus, according to University of California, Irvine health sciences researchers.
National Institutes of Health, National Multiple Sclerosis Society, Juvenile Diabetes Research Foundation, Wadsworth Foundation, Canadian Institutes for Health Research

Contact: Tom Vasich
tmvasich@uci.edu
949-824-6455
University of California – Irvine

May 14, 2007 Posted by | Irvine, Juvenile Diabetes, Multiple Sclerosis, University of California | 6 Comments

   

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