|
|
Climb National Information Centre for Metabolic Diseases
|
|
|
Subscribe and receive the E-Newsletter by Email
Previous Editions
Vol 1_No 9
|
Research ENews Vol 1 No 14 March 2008 Welcome to the National Information and Advice Centre for Metabolic Diseases Research News Sheet - Vol 1 No 14. The contents of this news sheet has been gathered from around the globe during our research to update our information on metabolic diseases. The contents are general and not specific to our cause.
Tweaking a Certain Gene Eases Fragile X Symptoms in Lab Tests on Mice Scientists may have found a genetic key to treating fragile X syndrome. Fragile X syndrome is the most common form of inherited mental retardation and is associated with autism. "These findings have major therapeutic implications for fragile X syndrome and autism," the researchers write in tomorrow's edition of Neuron. Such therapies aren't ready for use in people yet. In lab tests, the scientists tweaked the DNA of mice with fragile X syndrome. The goal was to make a certain mouse gene halve its production of a protein called mGluR5. Reducing production of that protein eased fragile X syndrome symptoms including seizures and problems with the eye, nerves, brain, memory, and body growth. "A simple way to conceptualize the constellation of findings is that fragile X syndrome is a disorder of excess ... and these excesses can be corrected by reducing mGluR5," write the researchers. They included graduate student Gul Dolen and Mark Bear, PhD, Picower Professor of Neuroscience and the director of the Picower Institute for Learning and Memory at the Massachusetts Institute of Technology (MIT). "It is remarkable that by reducing mGluR5 gene dosage by 50%, we were able to bring multiple, widely varied fragile X phenotypes [symptoms] significantly closer to normal," write the researchers. An MIT news release notes that while the experiment involved genetic engineering, drugs designed to do the same thing will soon be tested in people. SOURCES: Dolen, G, Neuron, 20, Dec 2007; vol 56: pp 955-962. News release, Massachusetts Institute of Technology. News release, Cell Press. WebMD Medical News Reviewed By Louise Chang, MD http://www.medicinenet.com/script/main/art.asp?articlekey=85964 Chemical Signals Go Awry in Fragile X Syndrome New information about how brain cells are affected in Fragile X syndrome -- the most common cause of inherited mental retardation -- has been uncovered. In the study, researchers at the University of Texas Southwestern Medical Center at Dallas examined mice to see how Fragile X syndrome affects communication between cells in the hippocampus, a part of the brain involved in learning and memory. The team found that two different chemical signals go awry in Fragile X syndrome. This suggests that drugs that interact with these chemical signals may offer a treatment. The study is published in the current issue of The Journal of Neuroscience. "I think we've discovered a core mechanism underlying Fragile X syndrome," senior author Dr. Kimberly Huber, an assistant professor of neuroscience, said in a prepared statement. "The more we know about how signaling mechanisms in the brain lead to normal memory and learning, the better we can understand what goes wrong in conditions such as Fragile X syndrome," Huber said. "Our research is laying the groundwork for such understanding and indicates a new area for research." Fragile X syndrome occurs mostly in males and affects about one in every 4,000 white males in the United States, according to the U.S. Centers for Disease Control and Prevention. Along with mental deficits ranging from mood disorders to severe mental retardation, people with the syndrome often have distinct physical traits, including an elongated face with protruding ears and hyperflexible joints. By Amanda Gardner HealthDay Reporter
-- Robert Preidt SOURCE: University of Texas Southwestern Medical Center at Dallas news release, 8 Jan. 2008 http://www.medicinenet.com/script/main/art.asp?articlekey=86414
Years-Long Search Unlocks Deadly Genetic Disease Ann Messer knew something was wrong while she was still pregnant with her second child. Her baby didn't move, except sometimes to roll over to one side of her body, leaving her stomach flat Her fears were confirmed when her son, Andrew, was born. "He had a very weak cry, very little muscle tone, he had contractures in his knee joints," Messer recalled. The doctors diagnosed congenital muscular atrophy. Andrew died at 5 months of age, in 1985. Two months later, a first cousin of Messer's, living in Evansville, Ind., gave birth to a baby boy with similar characteristics. That baby died at 10 months of age. "My mother saw him one time and said he was floppy, very limp, didn't move," Messer recalled. And unbeknownst to Messer at the time, yet another cousin, in a third branch of the family, this one living in New Orleans, had earlier given birth to two baby boys with the same condition. One died at 18 months and one lived to 18 years, although he needed a feeding tube and was confined to a wheelchair for all his short life. In all, four baby boys with the same condition were born in roughly a five-year span. They all died. Several years later, doctors were able to give the disease a more specific name: autosomal recessive spinal muscular atrophy (SMA). SMA is a neurodegenerative disorder occurring in children that involves severely weakened muscles and usually results in death within two years, often because muscles of the respiratory system can no longer support breathing. The X-linked form of the disease is passed unsuspectingly by healthy mothers to their sons. SMA made sense to Messer and her family, but they were baffled by the autosomal part of the diagnosis. "I'm not a genetics person, but I know that autosomal recessive means that both mothers and fathers have to be carriers [of the gene that causes the disease]," Messer said. "We started scratching our heads. What are the odds that all of us would have married somebody with the same recessive gene and our two mothers and our grandmother? I don't calculate odds very well, but I can tell that that's just a staggering amount." At about this time, another cousin, Patti, living in Houston, married and wanted to have children but was terrified after watching the devastation of her family. She sought genetic counseling. Enter Lisa Baumbach-Reardon, associate research professor of pediatrics and neurology at the University of Miami Miller School of Medicine, who was already researching a similar family in South Carolina. Baumbach-Reardon would spend 15 years searching for the genetic root of these family tragedies. "We started investigating and found all these other families, and then we spent many years trying to map the gene where it was on the X chromosome, and we were very sure about where it was, but we had no great breakthroughs or clues," Baumbach-Reardon recalled. "It was probably the biggest scientific experience of my career, and many times we were told to give up, but we didn't give up, because we knew in the end what we were working on was this terrible disease." This week, Baumbach-Reardon and her colleagues published the results of their quest in The American Journal of Human Genetics. A gene known as UBE1 is the cause of this rare, X-linked form of SMA. The gene lies at the top of a major biological pathway, the same pathway that has been implicated in Parkinson's and other neurodegenerative disorders. "It's the beginning of a pathway. If that doesn't work in the beginning, then nothing else works," Baumbach-Reardon explained. Tragically, all six women in Ann Messer's generation were carriers of the mutation -- a mutation that was enough to cause the disease, regardless of their husbands' genetic makeup. On Dec. 7, Baumbach-Reardon flew to Houston to meet with nine members of the family and tell them the scientists had finally located the gene responsible for their losses. "We met in a Sunday school room in my cousin's church," Messer said. "Dr. Baumbach flew in from Miami, bless her heart. She's sitting there looking at nine blank faces trying to explain Genetics 101." For the family, Messer said, "it gave a meaning and purpose to all of this heartache we've all gone through and gives us so much hope for so many more families, the diagnosis and the therapies that I'm sure they'll eventually develop, and prevention." Because the gene has links to Parkinson's disease, that offers hope that more progress will be made in preventing and treating that disease and others like it. "The thought of the agony and anguish that we went through, the sadness, that we can be a part to help thousands of families is just huge for us," Messer said. The knowledge gained from the Miami researchers' work has already benefited the family. One of Messer's nieces was found not to carry the mutation. "She can have children and not worry about it," Messer said. Dr. E. Darrell Crisp, associate professor of internal medicine and pediatrics at the Texas A&M Health Science Center College of Medicine and director of pediatric neurology at Scott & White Hospital in College Station, cared for Andrew Messer 23 years ago, although he was not involved with the new study. "Having a gene localization and a way of making a diagnosis... helps differentiate whether this is truly SMA or another disorder," Crisp said. "Another thing is, if it's the X-linked form of SMA, it can tell us whether a person in the family may be a carrier and if they are at risk. SOURCES: Lisa Baumbach-Reardon, Ph.D., associate research professor of pediatrics and neurology, University of Miami Miller School of Medicine; Ann Messer, Belton, Texas; E. Darrell Crisp, M.D., associate professor of internal medicine and pediatrics, Texas A&M Health Science Center College of Medicine, and director of pediatric neurology, Scott & White Hospital, College Station; 10. Jan. 2008, The American Journal of Human Genetics http://www.medicinenet.com/script/main/art.asp?articlekey=86338
Study Suggests Idebenone May Improve Neurological Function in Friedreich's Ataxia Results of a placebo-controlled, double-blind phase II study of the antioxidant idebenone in children with Friedreich's ataxia (FA) suggest that the treatment may lead to improvements in neurological function. It is the first placebo-controlled study to suggest that the neurological deterioration associated with this disease can be slowed or reversed. Several previous studies using low doses of idebenone have suggested that it may reduce the heart enlargement that frequently occurs with FA, and an open-label study of idebenone in early-stage FA patients found an improvement in neurological function that appeared related to drug levels. However, the new study is the first controlled trial to suggest a neurological benefit or a reduction in symptoms of the disease. FA is an inherited disease that causes progressive damage to the nervous system and other organs. It is caused by a gene defect that results in lower-than-normal levels of a protein called frataxin. The lack of frataxin impairs the function of mitochondria and triggers a type of chemical damage in cells that is called oxidative stress. Symptoms of FA usually begin between the ages of 5 and 15 and range from uncoordinated movements (ataxia) to speech problems, diabetes, scoliosis (abnormal curvature of the spine), and heart disease. Most people with FA eventually need a wheelchair. Currently there is no proven treatment that alters the progression or neurological symptoms of the disorder. “With hereditary neurodegenerative diseases, usually the best we hope for is to slow the progression of the disease. Here it looks like the drug may have actually reduced the manifestations of the disease,” says Kenneth Fischbeck, M.D., of the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland, who led the new study together with Nicholas Di Prospero, M.D., Ph.D. The report appears in the October issue of Lancet Neurology.[1]. The researchers studied idebenone in 48 children ages 9-17 who had genetically confirmed FA. Participants were divided into four groups. Three of the groups received fixed doses of idebenone, approximately equal to 5 mg/kg, 15 mg/kg, or 45 mg/kg, for 6 months. The fourth group received a placebo. The study was double-blind, meaning that neither the participants nor the researchers knew which patients were receiving the drug and which were receiving the placebo. The researchers tested the urinary levels of a chemical called 8-hydroxy-2'-deoxyguanosine (8OH2'dG), which is a marker of DNA damage from oxidative stress. They also used two scales to rate the severity of FA before and after treatment: the international cooperative ataxia rating scale (ICARS) and the Friedreich's ataxia rating scale (FARS). Parents of the children also completed surveys about the children's abilities to carry out activities of daily living (ADLs). After 6 months of treatment, the investigators found an indication of improvement in the ICARS scores that was related to the dose of idebenone. When participants who frequently used a wheelchair were excluded from the data analysis, the results were stronger. Participants who received the placebo had declines of approximately 2 points on the ICARS scale, while those on low-dose idebenone showed only slight improvement. In contrast, participants given the intermediate dose improved by about 4 points on average, and those given the high dose improved by almost 6 points. These changes amounted to a 10-17 percent reduction in symptoms from the baseline scores. The researchers also found dose-dependent improvements in the FARS and ADL scores, although those changes were not statistically significant. Improvements in eye movements and speech were the most marked changes seen in the ICARS scores, but all aspects of neurological function measured by the scale showed some improvement, the researchers say. The patients' 8OH2'dG levels at the beginning of the study were not elevated, in contrast to the results of previous studies. The levels also did not change significantly after idebenone treatment. This suggests that 8OH2'dG may not be a reliable biomarker for FA, the investigators say. The results also suggested that idebenone is well tolerated by most people, even at high doses. The majority of side effects were mild, while a few were moderate but appeared unrelated to the drug. One patient on the highest dose of idebenone developed a low white blood cell count that might have been related to the drug, but the problem resolved after treatment was discontinued. "FARA and the international Friedreich's ataxia community are extremely grateful for the tremendous service performed by the excellent and dedicated team at NIH/NINDS in conducting this phase II clinical trial and the phase I trial that preceded it. In this promising clinical trial, we see confirmation that the Friedreich's ataxia community, by working hard together and collaborating broadly, has indeed entered the treatment era. We eagerly await commencement of a phase III clinical trial of idebenone and the prospects of achieving the first approved treatment for this devastating disease," says Ronald J. Bartek, President of the Friedreich's Ataxia Research Alliance (FARA) in Springfield, Virginia. These findings may help to refine the design of other clinical trials for FA. A number of compounds are now moving into clinical trials for this disease. The new results can help investigators decide what subjects to include, the duration of treatment, and what outcome measures to look at, says Dr. Di Prospero. Also, the neurological improvements seen with high-dose idebenone in this study suggest that it may be useful for other diseases that include oxidative stress and/or mitochondrial abnormalities, including Huntington's disease and Alzheimer's disease, Dr. Fischbeck adds. Previous studies have tested idebenone for these diseases, but only at low doses. While the results of this study are encouraging, they are not definitive, Dr. Fischbeck cautions. Investigators need to conduct a phase III clinical trial to determine if the improvements seen in this study can be confirmed. One phase III trial is now underway in Europe, and a U.S.-based phase III study is in the planning stages. Researchers also need to further study idebenone in the laboratory to determine exactly how it works. Those studies may eventually lead to development of more potent drugs. The NINDS is a component of the National Institutes of Health (NIH) in Bethesda, Maryland, and is the nation’s primary supporter of biomedical research on the brain and nervous system. The NIH is comprised of 27 Institutes and Centers and is a component of the U. S. Department of Health and Human Services. It is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research, and investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov. -By Natalie Frazin [1]Di Prospero N, Baker A, Jeffries N, Fischbeck KH. "Neurological effects of high-dose idebenone in patients with Friedreich's ataxia: a randomized, placebo-controlled trial." Lancet Neurology, October 2007, Vol. 6, No. 10, pp. 878-886. http://www.ninds.nih.gov/news_and_events/news_articles/news_article_FA_idebenone.htm
Ongoing Neurofibromatosis Type 1 Studies Recruiting participants in the study Variation in Gene Expression in Neurofibromatosis Type Douglas Stewart, M.D., a medical geneticist at the National Institutes of Health, is investigating differences in disease severity among individuals and families with neurofibromatosis type 1 (NF1). The purpose of the study is to look at the genetic differences among individuals with NF1 to understand why some people with NF1 have more severe disease than other people, also with NF1. Individuals age 16 years and older diagnosed with NF1 may be eligible to participate in this study. Participants can either be the first member of their family affected or have a family history of the disease. Parents and affected siblings will also be invited to participate. The study will include a two-day visit to the NIH Clinical Center for a genetics evaluation, MRI of the spine, ultrasound of the heart, dental evaluation, photography and a blood draw. Medical evaluations will be free of charge and funding is available for travel expenses. Jennifer
Sloan, Ph.D., M.S.
Orphan Drug Designation Granted To OVATION's Clobazam For
The Adjunctive Treatment Of A Severe Form of Childhood Epilepsy OVATION Pharmaceuticals, Inc. was granted special status by the U.S. Food and Drug Administration (FDA) for clobazam as an adjunctive treatment for Lennox-Gastaut syndrome (LGS), one of the most severe forms of childhood epilepsy that frequently persists into adulthood. The FDA grants orphan drug designation to products that are intended to treat rare or "orphaned" diseases or conditions such as LGS, which is responsible for approximately three to 10 percent of all childhood epilepsies.3 For LGS patients, as with patients fighting other rare diseases, new treatments are few and far between, making this designation by FDA of significant importance. "LGS is a devastating and difficult to treat form of childhood epilepsy that often leads to some form of mental retardation and other behavioral problems over time," said Dr. Tim Cunniff, Vice President, Global Regulatory Affairs, Pharmacovigilance, and Clinical Quality Assurance from OVATION Pharmaceuticals. "Clobazam is being developed to provide physicians with an additional treatment option for patients with LGS, for whom there are very few safe and effective treatments." Clobazam has been designated as an orphan drug by the FDA under the auspices of the Orphan Drug Act. The Act, which marks its 25th Anniversary on January 4, 2008, provides incentives to sponsors that develop therapies intended to treat orphan conditions, which are classified as any condition or disease that affects less than 200,000 patients per year in the United States. It is estimated that there are more than 6,000 rare diseases affecting 25 million Americans.1,2 In a Phase 2 trial, clobazam significantly reduced drop seizures as compared to baseline. Drop seizures are considered the most debilitating of the LGS seizures types and can result in severe trauma to the brain and body. The majority of adverse events (AEs) observed in this trial were mild or moderate in severity. No serious AEs resulted in premature discontinuation of drug treatment. Clobazam is currently being evaluated in a late-stage clinical trial as an adjunctive treatment for LGS. For more information about the ongoing trial, please visit: http://clinicaltrials.gov/ About Lennox-Gastaut Syndrome A rare and catastrophic form of epilepsy, LGS is characterized by several seizure types and represents approximately three to 10 percent of all childhood epilepsies.3 Onset typically occurs between three and 10 years of age. Drop attacks are frequent in LGS and responsible for most injuries associated with falls. Up to 90 percent of children with LGS are affected by mental retardation and these children commonly experience behavioral and sleep disturbances as well.4 About Clobazam Clobazam is a 1,5-benzodiazepene and has a distinctive chemical structure as compared to other currently available benzodiazepines. It was initially developed to reduce the adverse effects associated with 1,4-benzodiazepines while still maintaining efficacy. In animal models, clobazam has been shown to work both by intensifying gamma-aminobutyric acid (GABA)-mediated inhibitory effects and by increasing activity of glutamate transporters. Clobazam is widely available with approvals in more than 100 countries for various uses in both children and adults, including the adjunctive treatment of epilepsy and anxiety. Though not currently approved for any use in the U.S., OVATION plans to seek FDA approval for clobazam as adjunctive treatment for patients with LGS. To support this development program, a global multicenter, Phase 3 clinical trial is currently underway and enrolling patients. Clobazam is one of the key products in OVATION's CNS development pipeline. The company is advancing its near-term pipeline on other fronts as well. In July 2007, the company initiated a pivotal clinical trial to evaluate a novel intravenous formulation of carbamazepine, a widely used oral antiepileptic drug, in adult patients with epilepsy. The launch of another oral anticonvulsant for rare and refractory epilepsies is anticipated in 2008. About OVATION Pharmaceuticals OVATION is a fast-growing biopharmaceutical company that develops, manufactures and markets medically necessary therapies to satisfy unmet medical needs for patients with severe illnesses. Headquartered in Deerfield, Ill., with products available in more than 85 countries, OVATION is committed to having a significant impact on patients' lives through its focus on central nervous system (CNS), hematology/oncology, and hospital-based therapies. The five new launches the company expects over the next five years will be fueled by its late-stage CNS pipeline, which is one of the most robust in the industry. OVATION has been recognized for excellence in the global pharmaceutical and biotechnology industries with the 2006 and 2007 "Pharma Company of the Year" award from Scrip magazine for small to mid-sized enterprises. More information about the company, its products and full prescribing information may be found at http://www.ovationpharma.com/.
http://www.ovationpharma.com/. Climb provides the above third-party links as a convenience and makes no assurances and/or warranties, implied or otherwise, and is not responsible for the information you receive from the linked sites or any supporting information related to the subject. The inclusion of any link does not imply endorsement of Climb or the sites or the information contained therein. Climb is not responsible for the contents of any linked site or any link contained in a linked site or any changes or updates to such sites. This newsletter is provided for information only.
|
|
