NF1 and a Cholesterol lowering drug

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HREF="id300.htm" TARGET="_top" TITLE="Clues to Nf1">Clues to Nf1</A></div> <div> NF1 and a Cholesterol lowering drug </div> <div> Research News</div> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="626" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER BGCOLOR=#008080 HEIGHT= 32 WIDTH="622"><bR> <bR> </tD> </tR> </TABLE></div> <bR> <div> <TABLE BORDER="0" CELLPADDING="1" CELLSPACING="1" WIDTH="626" BORDERCOLORLIGHT="#C0C0C0" BORDERCOLORDARK="#808080" FRAME="VOID" RULES="NONE" HSPACE="0" VSPACE="0" > <tR> <tD VALIGN=CENTER HEIGHT= 265 WIDTH="622"><div> November 09, 2005</div> <div> CTF funded research shows promise for statins in reversing NF1 learning disabilities</div> <div> Dr. Alcino Silva and colleagues from the at the David Geffen School of Medicine at the University of California, Los Angeles reported this week in the journal <FONT SIZE="3" COLOR="#330000" FACE="Arial" ><I>Current Biology</I></FONT><I> </I>a report showing that the commonly prescribed cholesterol-lowering drug lovastatin can reverse learning and memory problems in mouse models of NF1. These studies are significant as over half of persons with NF have learning disabilities; in addition these findings could be relevant in developing treatments for the 5% of persons worldwide who suffer from some learning disabilities. </div> <bR> <div> The Food and Drug Administration has agreed to allow lovastatin clinical trials in patients with neurofibromatosis-1 to go forward immediately. These studies were funded in part by the Children’s Tumor Foundation. </div> <bR> </tD> </tR> </TABLE></div> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B>MORE:</B></div> <bR> <div> Public release date: 7-Nov-2005</div> <bR> <div> <B>NF1 and a cholesterol lowering drug </B></div> <bR> <div> Contact: Elaine Schmidt</div> <div> <A HREF="mailto:eschmidt@mednet.ucla.edu" TARGET="_top" TITLE="mailto:eschmidt@mednet.ucla.edu"><U>eschmidt@mednet.ucla.edu</U></A></div> <div> 310-794-2272</div> <div> <A HREF="http://www.newsroom.ucla.edu/" TARGET="_blank" TITLE="http://www.newsroom.ucla.edu/"><U>University of California - Los Angeles</U></A><FONT SIZE="3" COLOR="#000000" FACE="Arial" ><A HREF="http://www.newsroom.ucla.edu/" TARGET="_blank" TITLE="http://www.newsroom.ucla.edu/"> </A></FONT></div> <DIV ALIGN="LEFT"></DIV> <div> <B>Recreating 'Flowers for Algernon' with a happy ending</B></div> <div> UCLA scientists use statins to overcome learning disabilities in mice</div> <bR> <div> In a surprise twist that recalls the film classic "Flowers for Algernon," but adds a happy ending, UCLA scientists used statins, a popular class of cholesterol drugs, to reverse the attention deficits linked to the leading genetic cause of learning disabilities. The Nov. 8 issue of Current Biology reports the findings, which were studied in mice bred to develop the disease, called neurofibromatosis 1 (NF1). </div> <bR> <div> The results proved so hopeful, that the Food and Drug Administration approved the use of the drugs in three clinical trials currently under review to test the effect of statins in children and adults born with NF1. The findings could help the estimated 35 million Americans who struggle with learning disabilities. </div> <bR> <div> "Learning disabilities and mental retardation each affect five percent of the world population," said Dr. Alcino Silva, professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. "Currently, there are no treatment options for these people. That's why our findings are so exciting from a clinical perspective." </div> <bR> <div> In an earlier study, Silva and his colleagues linked NF1's learning problems to a protein called Ras, a protein that regulates how brain cells talk to each other. This communication is what enables learning to take place. The NF1 mutation creates hyperactive Ras, which disrupts cellular conversation and undermines the learning process. </div> <div> "The act of learning creates physical changes in the brain, like grooves on a record," said Silva. "But surplus Ras tips the balance between switching signals on and off in the brain. This interrupts the delicate cell communication needed by the brain to record learned information." </div> <bR> <div> The UCLA team began searching for a safe drug that would zero in on Ras and overcome its hyperactivity without causing harmful side effects over long-term use. </div> <bR> <div> "It became something of a Quixotic quest -- an impossible dream," Silva admitted. "We thought, 'Wouldn't it be nice to find a drug that is already FDA-approved, safe for lifetime use and could be tested in mice and humans with NF1?' Fortunately, our optimism was rewarded." </div> <bR> <div> It took a medical student in Silva's lab to identify the drug and connect it with NF1. Steve Kushner, a scholar in UCLA's MD/PhD program, learned in a clinical rotation about statins, the drugs already prescribed to millions of people worldwide to lower cholesterol. </div> <bR> <div> "Steve raced into my lab and shared what he'd learned: statins work on the Ras protein that is altered by NF1 and play a key role in learning and memory," recalled Silva. "It was the researcher's equivalent of finding a suitcase stuffed with a million dollars." </div> <bR> <div> Statin drugs lower cholesterol by blocking the effects of certain fats. Because Ras requires fat to function, less fat results in less Ras. With reduced Ras activity, the brain cells are able to communicate properly in mice with NF1, allowing normal learning to take place. </div> <bR> <div> "NF1 interrupts how cells talk to each other, which results in learning deficits," said Silva. "Statins act on the root of the problem and reverse these deficits. This enables the process of learning to physically change the brain and create memory." </div> <bR> <div> Silva's lab tested the effects of statins on mice that were bred with the NF1 mutation. The animals displayed the same symptoms as people with NF1: attention deficits, learning problems and poor physical coordination. </div> <div> First author Weidong Lee, a UCLA postdoctoral fellow, ran three tests to compare the behavior of NF1 mice treated with statins to NF1 mice who received a placebo. Then he compared both groups to normal mice. </div> <div> First, he trained the mice to follow a blinking light in order to find a food reward. The NF1 mice on statins showed a 30 percent improvement in their ability to pay attention, outperforming the normal mice. </div> <bR> <div> Second, he trained the mice to memorize spatial clues in order to navigate a water maze and swim to a platform. The normal animals learned to find the platform in seven days; the NF1 mice took 10. After receiving statins, the NF1 mice outraced the normal mice. </div> <bR> <div> Third, Lee tested coordination by training the mice to balance while running on a rotating log, which gradually increased in speed. At first, the NF1 mice would jump off as the log spun faster. But statin therapy enabled the NF1 mice to perform as well as their normal counterparts. </div> <bR> <div> "This is mind-blowing – we think we have a real fundamental reason to be optimistic," explained Silva. "Here is a drug that affects a key learning and memory pathway, and completely rescues the most common genetic cause for learning disabilities. We don't have to do extensive clinical trials for toxicity or safety – these were already completed for other uses." </div> <DIV ALIGN="LEFT"></DIV> <div> ### </div> <div> NF1 afflicts one in 4,000 people, about one million people worldwide. The disorder usually surfaces in childhood, when affected youngsters develop learning disabilities and behavioral problems often mistaken for Attention Deficit Disorder. Trademark cafe-au-lait spots and disfiguring nerve tumors appear under the skin in the late teens and early adulthood. </div> <div> UCLA's study was funded by the National Institute of Neurological Diseases and Stroke, the Neurofibromatosis Foundation, Neurofibromatosis, Inc., and a private donation by Ms. Carol Moss Spivak. </div> <bR> <DIV ALIGN="LEFT"></DIV> <div> <B>MORE:</B></div> <div> Contact: Heidi Hardman</div> <div> <A HREF="mailto:hhardman@cell.com" TARGET="_top" TITLE="mailto:hhardman@cell.com"><U>hhardman@cell.com</U></A></div> <div> 617-397-2879</div> <div> <U>Cell Press</U><FONT SIZE="3" COLOR="#000000" FACE="Arial" > </FONT></div> <div> <B>A commonly prescribed drug reverses learning and attention deficits in a mouse model of the genetic disorder Neurofibromatosis type I</B></div> <div> This week, researchers report evidence that a statin drug already shown to be safe for use in humans has proven effective at correcting cell-cell communication and curing learning disfunction in a mouse model of Neurofibromatosis type I, a human genetic disorder that causes learning disabilities in millions of people worldwide. </div> <bR> <div> Learning disabilities affect 5% of the world's population, have a profound impact on countless lives, and cost billions of dollars, but there is little or nothing that we are currently able do to prevent or treat this enormous problem. At the heart of this challenge is our lack of understanding of the mechanisms underlying this complex class of brain problems. In an effort to understand these disorders and develop treatments, Dr. Alcino Silva and colleagues at UCLA have focused research on the study of the most common genetic cause for learning disabilities: Neurofibromatosis type I (NF1). The idea behind the NF1 research is that if we understand this particular learning disability, which is caused by a single defective gene, and manage to develop effective and sustainable treatments, we may be able to use the information learned to tackle this general class of learning and memory problems. </div> <bR> <div> Because of the difficulties and limitations of studying mechanisms of memory in human patients, the researchers decided to study NF1 in mice. The scientists had previously shown that mice with the mutations that cause NF1 in human patients possess many of the features of this complex disorder, including deficits in spatial learning, attention, and motor coordination. Studies of these mutant mice showed that the learning deficits are caused by the overactivity of a molecule called Ras, causing an imbalance between signals that activate brain cells and those that inhibit them, and leading to deficits in cell-cell communication needed for learning. </div> <div> The work reported by Silva and colleagues this week in Current Biology demonstrates that a commonly prescribed statin drug, Lovastatin, can reverse the overactivity of Ras, decrease inhibition, repair the cell-cell communication deficits, and cure the learning disabilities of the adult Nf1 mutant mice. These findings are tremendously exciting because they suggest that the disabling learning deficits associated with NF1, a disorder that affects one in three thousand people world-wide, could be cured with a class of relatively safe drugs (statins) that millions of people have taken for extended periods of time in the last 20 years. Importantly, the findings also demonstrate that contrary to popular belief, the cognitive deficits associated with this disorder are not irreversible developmental deficits, since a limited treatment in adult mice can effectively reverse this condition. Because the mechanisms of NF1 function are similar in mice and men, these findings suggest that statins will be an effective strategy to treat NF1 in humans. </div> <DIV ALIGN="LEFT"></DIV> <div> ### </div> <div> The researchers included Weidong Li, Yijun Cui, Steven A. Kushner, Robert A.M. Brown, J. David Jentsch, Paul W. Frankland, Tyrone D. Cannon, and Alcino J. Silva of the University of California, Los Angeles in Los Angeles, California. This study was funded by grants from the NIH (R01 NS38480), Neurofibromatosis, Inc. (National, Illinois, Mass Bay Area, Minnesota, Arizona, Kansas and Central Plains, Mid-Atlantic, and Texas chapters), the Merck, and the National Neurofibromatosis Foundation (NNF) to A.J.S. Y.C. was supported by a Young Investigator Award from NNF. </div> <bR> <DIV ALIGN="LEFT"></DIV> <div> ALSO VISIT: <FONT SIZE="1" COLOR="#000000" FACE="Arial" ><A HREF="http://www.newsday.com/news/health/ny-hshow4504479nov09,0,2846720.story?coll=ny-health-headlines" TARGET="_blank" TITLE="http://www.newsday.com/news/health/ny-hs">http://www.newsday.com/news/health/ny-hshow4504479nov09,0,2846720.story?coll=ny-health-headlines</A></FONT></div> <div> <A HREF="index.htm" TARGET="_top" TITLE="NF TEAM"><IMG SRC="05257250.jpg" border=0 width="87" height="37" ALIGN="BOTTOM" HSPACE="0" VSPACE="0"></A></div> <bR> </td> </tr></table></body>