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Archive - Mar 18, 2012

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Bone Marrow Transplant Arrests Symptoms in Model of Rett Syndrome

A paper published online on March 18, 2012 in Nature describes the results of using bone marrow transplant (BMT) to replace faulty immune system cells in models of Rett syndrome. The procedure arrested many severe symptoms of the childhood disorder, including abnormal breathing and movement, and significantly extended the lifespan of Rett mouse models. Exploring the function of microglia deficient in methyl-CpG binding protein 2 (Mecp2), the protein encoded by the "Rett gene," principal investigator Jonathan Kipnis, Ph.D. and his team at the University of Virginia School of Medicine uncovered a completely novel approach to this devastating neurological syndrome. Rett syndrome, the most physically disabling of the autism spectrum disorders, is caused by random mutations in the gene MECP2. Predominantly affecting girls, symptoms usually manifest between 6 and 18 months of age, when a frightening regression begins. Children lose acquired language skills and functional hand use; movement deteriorates as other Rett symptoms appear. These may include disordered breathing, Parkinsonian tremors, severe anxiety, seizures, digestive and circulatory problems, and a range of autonomic nervous system and orthopedic abnormalities Although most children survive to adulthood, many are wheelchair-bound, rely on feeding tubes, are unable to communicate, and require total, lifelong care. Dr. Kipnis was drawn to Rett syndrome from his perspective as a neuroimmunologist. "What began as intellectual curiosity," he explains, "has become an intense personal commitment to studying the correlation between neurological function and the immune system in Rett syndrome.

Single Gene Mutation Can Lead to Uncontrolled Obesity

Researchers at Georgetown University Medical Center have revealed how a mutation in a single gene is responsible for the inability of neurons to effectively pass along appetite suppressing signals from the body to the right place in the brain. What results is obesity caused by a voracious appetite. Their study, published online on March 18, 2012 on Nature Medicine's website, suggests there might be a way to stimulate expression of that gene to treat obesity caused by uncontrolled eating. The research team specifically found that a mutation in the brain-derived neurotrophic factor (Bdnf) gene in mice does not allow brain neurons to effectively pass leptin and insulin chemical signals through the brain. In humans, these hormones, which are released in the body after a person eats, are designed to "tell" the body to stop eating. But if the signals fail to reach correct locations in the hypothalamus, the area in the brain that signals satiety, eating continues. "This is the first time protein synthesis in dendrites, tree-like extensions of neurons, has been found to be critical for control of weight," says the study's senior investigator, Baoji Xu, Ph.D., an associate professor of pharmacology and physiology at Georgetown. "This discovery may open up novel strategies to help the brain control body weight," he says. Dr. Xu has long investigated the Bdnf gene. He has found that the gene produces a growth factor that controls communication between neurons. For example, he has shown that during development, BDNF is important to the formation and maturation of synapses, the structures that permit neurons to send chemical signals between each other. The Bdnf gene generates one short transcript and one long transcript.

BRAF-Inhibitor Shows Promise in Treatment of Some Metastatic Melanomas

An international team of researchers from the United States and Australia, including researchers at the Moffitt Cancer Center in Tampa, Florida, have found that the oral BRAF inhibitor vemurafenib (PLX4032) when tested in a phase II clinical trial offered a high rate of response in patients with previously treated metastatic melanoma and who had the BRAF mutation. More than 50 percent of the patients in the trial had positive, prolonged responses and a median survival of almost 16 months. The study was published in the February 23, 2012 issue of the New England Journal of Medicine. According to study co-author Jeffrey S. Weber, M.D., Ph.D., director of the Donald A. Adam Comprehensive Melanoma Research Center at Moffitt, approximately 50 percent of melanomas harbor the activating (V600) mutation threonine protein kinase B-RAF. Unfortunately, treatment options for these patients are "limited." The BRAF inhibitor vemurafenib had been found effective in phase I and phase III trials. However, to determine the overall response rate in previously treated stage IV melanoma patients, the researchers designed a multi-center, phase II trial with 132 patients with previously treated BRAF V600-mutant metastatic melanoma. The trial was designed by senior academic authors and representatives of the trial sponsor, Hoffman-La Roche, and was open to adults over the age of 18 with histologically proven stage IV melanoma, progressive disease, and at least one prior systemic treatment. "Few patients with metastatic melanoma bearing the BRAF V600 mutation have a response to systemic chemotherapies," said Dr. Weber. "Additionally, most have a median survival of only 6 to 10 months.