Gene therapy prevents the onset of diabetic symptoms in mice

Using state-of-the-art gene therapy techniques, University of Pittsburgh investigators have successfully prevented the onset of elevated blood sugar, or hyperglycemia, in diabetes-prone mice by inserting a gene encoding for a cytokine -- a protein that stimulates or inhibits the proliferation or function of immune cells -- into their insulin-producing cells. According to the investigators, these findings, which are being presented at the American Society of Gene Therapy Annual Meeting in Baltimore, May 31 to June 4, have significant implications for the prevention of type 1 diabetes. More than 700,000 Americans have type 1 diabetes, an autoimmune disorder in which the body errantly attacks the cells of the insulin-producing cells of the pancreas, causing chronic hyperglycemia and complications such as blindness, kidney failure, heart disease and nerve damage. Previously known as juvenile diabetes, type 1 diabetes is usually diagnosed at a very early age but is sometimes not diagnosed until the individual reaches adulthood. In this study, the Pitt researchers used a gene-delivery vehicle known as an adeno-associated virus to insert genes for either of two cytokines, interleukin-4 (IL-4) or interleukin-10 (IL-10), into the insulin-producing beta cells of non-obese diabetic (NOD) mice. Following gene delivery, expression of IL-4 in beta cells prevented the onset of hyperglycemia in NOD mice, whereas beta cell expression of IL-10 accelerated the onset of hyperglycemia. According to lead author Khaleel Rehman Khaja, Ph.D., senior research associate, department of molecular genetics and biochemistry, University of Pittsburgh School of Medicine, results from this animal study suggest that gene therapy is a viable method for preventing the onset of type 1 diabetes in genetically at-risk people. "We know that the prevention of type 1 diabetes requires early intervention in the autoimmune process directed against beta cells of the pancreatic islets. Although the exact mechanism is still under investigation, we believe the protection we observed in our study is due to IL-4 stimulating an increase in regulatory T cells, which are known to suppress the activation of the immune system. However, the most important aspect of our study is that we've shown it is now possible to efficiently insert genes into beta cells in a living organism, allowing us to analyze the effects that different gene products have on the progression of type 1 diabetes," he explained. http://www.hhmi.org/news/winslow_crabtree20060606.html A New Way to Build Bone Howard Hughes Medical Institute (HHMI) researchers at Stanford University have found that they can increase bone mass in mice by tweaking the shape of a regulatory protein. HHMI investigator Gerald Crabtree and HHMI predoctoral fellow Monte Winslow report that slightly increasing the activity of a protein called NFATc1 causes massive bone accumulation, suggesting that NFATc1 or other proteins that regulate its activity will make good targets for drugs to treat osteoporosis. They report their findings in a study published in the June 6, 2006, issue of Developmental Cell. In vertebrates, bone is constantly being formed and being broken down throughout life. Cells called osteoclasts continuously degrade bone, while cells called osteoblasts replenish it. “Ideally, they are perfectly balanced,” said Crabtree, the senior author of the study. “Over the course of a lifetime, if everything goes well, we'll maintain almost exactly identical bone mass.” However, if the balance is upset, and more bone is destroyed than formed, osteoporosis results, increasing the risk of fractures. The new study arose from the researchers' curiosity about reports that patients who were treated with the drug cyclosporine—often given to suppress the immune system before organ transplants—tend to lose bone mass. Those patients were also at increased risk of bone fractures, said first author Winslow, who led the study as an HHMI predoctoral fellow in Crabtree's lab. Winslow is now working as a postdoctoral fellow in the lab of HHMI investigator Tyler Jacks at the Massachusetts Institute of Technology. http://www.eurekalert.org/pub_releases/2006-06/acs-afn060506.php A fundamentally new approach to improving cancer chemotherapy A new strategy for getting anti-cancer drugs to kill cancer cells, without causing serious harm to normal cells in the body, is reported in the current [June] issue of ACS Chemical Biology, a monthly peer-reviewed journal of the American Chemical Society. The approach, tested in laboratory experiments with several existing anti-cancer drugs, could offer substantial benefits for cancer patients, according to Jeffrey P. Krise, Ph.D. Krise led a group of pharmaceutical and medicinal chemists at the University of Kansas at Lawrence who did the research. The new approach would allow anticancer drugs to accumulate in both normal and malignant cells. The drugs, however, would be tweaked by giving them "basic" chemical properties. In chemistry, "basic" means an alkaline substance like baking soda or laundry detergent, which has properties opposite those of acidic substances. Normal cells simply isolate anti-cancer drugs with basic properties, greatly reducing the toxic effects. Cancer cells, in contrast, have an impaired ability to isolate basic substances, and get hit with a full blast of toxicity. "It could allow cancer patients to tolerate higher and more effective doses of chemotherapy before normal cells are damaged to an extent that causes serious side effects and cessation of therapy," Krise said. "The approach is completely different from previous attempts that were designed to deliver drugs only to cancer cells and not normal cells." "The results of our studies should lead to the development of rationally designed molecules that are more selective and produce fewer side effects," Krise explained. "Importantly, this technology can also be used to modify existing drugs and increase their selectivity." Krise's report describes a number of existing anti-cancer drugs that have basic properties, and notes that the new findings may provide the first explanation of why these drugs are so effective. "There is obviously much more work to be done in order for the impact of the work to be fully appreciated and accepted," Krise said. "We are hopeful, at the current time, that this technology will have broad applicability." The research team included Muralikrishna Duvvuri, Ph.D., Samidha Konkar, Ph.D., Kwon Ho Hong, Ph.D., and Brian S. J. Blagg, Ph.D. "Source":[ http://www.eurekalert.org/pub_releases/2006-06/uopm-gtp053106.php]

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