In a surprise twist thatrecalls the film classic "Flowers for Algernon," but adds a happy ending, UCLAscientists have discovered that statins, a popular class of cholesterol drugs,overcome the mutation linked to the leading genetic cause of learning disabilities.The Nov. 8 issue of Current Biology reports the findings, which were studied inmice bred to develop the disease, called neurofibromatosis 1 (NF1).
The results proved so hopeful that the Foodand Drug Administration approved the use of the drugs in three clinical trialscurrently under review to test the effect of statins in children and adultsborn with NF1. The findings could help the estimated 35 million Americans whostruggle with learning disabilities.
"Learningdisabilities and mental retardation each affect 5 percent of the worldpopulation," said Dr. Alcino Silva, professor of neurobiology, psychiatry andpsychology at the David Geffen School of Medicine at UCLA. "Currently, thereare no treatment options for these people. That's why our findings are soexciting from a clinical perspective."
Inan earlier study, Silva and his colleagues linked NF1's learning problems toRas, a protein that regulates how brain cells talk to each other. Thiscommunication is what enables learning to take place. The NF1 mutation createshyperactive Ras, which disrupts cellular conversation and undermines thelearning process.
"Theact of learning creates physical changes in the brain, like grooves on arecord," Silva said. "But surplus Ras tips the balance between switchingsignals on and off in the brain. This interrupts the delicate cellcommunication needed by the brain to record learned information."
TheUCLA team began searching for a safe drug that would zero in on Ras and reduceits levels without causing harmful side effects over long-term use.
"It became something of aquixotic quest — an impossible dream," Silva admitted. "We thought, 'Wouldn'tit be nice to find a drug that is already FDA-approved, safe for lifetime useand could be tested in mice and humans with NF1?' Fortunately, our optimism wasrewarded."
Ittook a medical student in Silva's lab to identify the drug and connect it withNF1. Steve Kushner, a scholar in UCLA's M.D./Ph.D. program, learned in aclinical rotation about statins, the drugs already prescribed to millions ofpeople worldwide to lower cholesterol.
"Steveraced into my lab and shared what he'd learned: Statins work on the Ras proteinthat is altered by NF1 and play a key role in learning and memory," Silva said."It was the researcher's equivalent of finding a suitcase stuffed with amillion dollars."
Statindrugs lower cholesterol by blocking the effects of certain fats. Because Rasrequires fat to function, less fat results in less Ras. With reduced Rasactivity, the brain cells are able to communicate properly in mice with NF1,allowing normal learning to take place.
"NF1interrupts how cells talk to each other, which results in learning deficits,"Silva said. "Statins act on the root ofthe problem and reverse these deficits. This enables the process of learning tophysically change the brain and create memory."
Silva'slab 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.
Firstauthor Weidong Lee, a UCLA postdoctoral fellow, ran three tests to compare thebehavior of NF1 mice treated with statins to NF1 mice who received a placebo.Then he compared both groups to normal mice.
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 payattention, outperforming the normal mice.
Second,he trained the mice to memorize spatial clues in order to navigate a water mazeand swim to a platform. The normal animals learned to find the platform inseven days; the NF1 mice took 10. After receiving statins, the NF1 miceoutraced the normal mice.
Third, Lee tested coordination by training the miceto 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 performas well as their normal counterparts.
"This is mind-blowing — we think we have a realfundamental reason to be optimistic," Silva said. "Here is a drug that affectsa key learning and memory pathway, and completely rescues the most commongenetic cause for learning disabilities. We don't have to do extensive clinicaltrials for toxicity or safety — these were already completed for other uses."
NF1 afflicts one in 4,000 people, about 1million people worldwide. The disorder usually surfaces in childhood, whenaffected youngsters develop learning disabilities and behavioral problems oftenmistaken for Attention Deficit Disorder. Trademark cafe-au-lait spots anddisfiguring nerve tumors appear under the skin in the late teens and earlyadulthood.
UCLA'sstudy was funded by the National Institute of Neurological Diseases and Stroke,the Children's Tumor Foundation, Neurofibromatosis Inc. and a private donationby Carol Moss Spivak.