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Cholesterol Drug May Also Help Learning Disabilities

UCLA researchers say lovastatin reverses the condition in mice. Three clinical trials on humans have been approved and will begin within weeks.

November 08, 2005|Thomas H. Maugh II | Times Staff Writer

Lovastatin, a widely used cholesterol-lowering drug, reverses common learning disabilities in mice, offering the first hope for a treatment of the problem in humans, UCLA researchers reported Monday.

Three separate human trials in children and adults will begin within weeks at UCLA and other U.S. and European locations, said Dr. Alcino J. Silva, a neurobiologist at UCLA and the lead author of a paper appearing in the journal Current Biology.

"Currently, there are no treatment options for these people," Silva said. "That's why our findings are so exciting from a clinical perspective."

Lovastatin, trade-named Mevacor, is one of a family of drugs known collectively as statins that have revolutionized the treatment of high cholesterol. The drugs, first introduced in the 1990s, are taken daily by millions of people at risk for heart disease and other problems, and have been widely recognized as safe.

The learning problems studied by the researchers were caused by a genetic defect called neurofibromatosis 1, the most common genetic cause of learning disabilities. It affects 1 in every 3,000 to 4,000 people -- more than a million worldwide.

The learning disabilities include poor attention spans, difficulties in carrying out tasks involving spatial abilities and problems learning new tasks.

Lovastatin also may be useful in a much larger group of people because the underlying molecular disorders in other types of learning disabilities may be similar, Silva said. As much as 5% of the population is learning disabled, and lovastatin may be useful in treating many of them, he said.

"We cannot demonstrate it rigorously, but we have many reasons to believe that it is very promising for these other categories as well," Silva said.

The key to the discovery is a protein called ras, which regulates how brain cells talk to one another.

Silva and his colleagues had previously shown that the genetic mutations associated with neurofibromatosis 1 lead to an excess production of ras, which inhibits the brain's ability to record newly learned information.

The team searched for a drug that could interfere with the excess ras, but had little success, Silva said. Then one of his former students, Steve Kushner, learned during a medical school rotation that statins can interfere with ras.

"He came back into my office late at night and said, 'I think I have something that might work,' " Silva said.

Statins interfere with ras by reducing the level of fats found in blood, known as lipids, which are required by ras to carry out its function.

Postdoctoral fellow Weidong Li tested the theory in Silva's lab using specially bred rats that had the neurofibromatosis 1 mutation and previously had been shown to have learning problems similar to those seen in humans with the disorder.

In one test, Li trained adult mice with the mutation to follow a blinking light to obtain a food reward. After the animals received lovastatin, their performance improved 30%, so that they outperformed normal mice. Two other tests provided similar results.

"This is mind-blowing," Silva said. "We think we have a real, fundamental reason to be optimistic.... Now we are ready to go and treat the human disorder."

The initial trials will focus on people with neurofibromatosis 1, but Silva believes lovastatin might eventually be useful for others as well.

"Ras has a central role in learning and memory," he said. Lovastatin "may be a safe way of increasing cognitive function that may go beyond neurofibromatosis 1."

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