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Researchers Report Promising Treatment for 2 Heart Ailments

For the first time, researchers have found a way to treat two deadly heart ailments that are caused by a protein that folds into an abnormal shape.While the treatment is tailored to the two forms of heart disease, it is based on principles that may lead to similar therapies for other conditions caused by misfolded proteins, including Alzheimer's disease, Parkinson's disease, adult-onset diabetes and the human form of mad cow disease.Encouraged by tests on animals and in healthy human volunteers, the researchers are about to begin clinical trials on patients with the two ailments, one that afflicts a million African-Americans and another that is found in up to 15 percent of all Americans over the age of 80. In both diseases, a normal protein that ferries nourishing factors to heart tissue assumes an abnormal shape. Over time, these misshapen or misfolded proteins accumulate into sticky clumps of material that fatally clog the heart.The treatment, described in Friday's issue of the journal Science, involves giving patients a simple "small molecule" drug that stops the misfolding process in its tracks, said Dr. Jeffery W. , a chemist at the Scripps Research Institute in La Jolla, Calif., who carried out the research.Scientists not connected with the research called the findings unusually exciting. "This work provides an inspiring example to us all," said Dr. Lindquist, director of the Whitehead Institute at the Massachusetts Institute of Technology who studies protein misfolding in yeast. "Mountainous problems that seemed insurmountable 10 years ago are being scaled on all sides."Dr. Dobson, a chemist at Cambridge University in England, said this was the first time anyone had found a substance to stop a protein-folding disease before it gets under way. Many people are trying to treat such diseases by interfering with the abnormal proteins at a later stage, he said, but such treatments may be too late because by then the proteins have formed clumps.Dr. said the new type of treatment could be used with any misfolded protein that interacts with another protein or can bind readily to small molecules. The search for such proteins is under way in laboratories all over the world.For example, Dr. Fred Cohen, a molecular biophysicist at the University of California at San Francisco, says his team is developing a simple molecule that binds to the proteins called prions and stops them from misfolding early in the process. Misfolded prions give rise to a host of diseases, including Creutzfeldt-Jakob disease, the human form of mad cow.The idea that 20 or more human diseases result from misfolded proteins is fairly recent. Proteins are born as floppy strings of molecules that quickly fold into tight packages with precise shapes that determine their function. For reasons that are not yet well understood, some proteins have a tendency to misfold into a second shape involving long sheets that stick together.When the cell's machinery for clearing away misfolded proteins slows down, many more proteins start forming these sheets and get stuck in that folding pattern. Over time, they accumulate into sticky fibrils or plaque.Each disease is caused by a different abnormally folded protein or protein fragment that builds up in the brain, skeletal tissue or organs. Sometimes a protein misfolds sporadically, especially as people get older. Misfolding is also caused by genetic mutations, or it can be transmitted between individuals when one eats the infected nervous tissue of another, even across species.Dr. and his colleagues study a collection of diseases that occur when a protein called transthyretin misfolds and builds up in heart, muscle or peripheral nerves.At least 80 mutations cause transthyretin diseases, Dr. said. Most are rare, affecting just a thousand people worldwide. But one disease, familial amyloid cardiomyopathy, affects about a million African-Americans, most of them men. Another disease, senile systemic amyloidosis, clogs the heart tissues of 10 to 15 percent of people over age 80.Transthyretin protein is made in the liver, where it picks up thyroid hormone and vitamin A and carries them via the bloodstream to tissues all over the body.The normal protein is made of four subunits, Dr. said. In most forms of the disease, a gene that makes two of those subunits is mutated so that the entire protein is less stable. The units tend to come apart and reassemble into fibrils.The only existing cure for these diseases is a liver transplant. The donated tissue provides a healthy gene in place of the mutated one. That strategy, however, does not always work and is ineffective in both these forms of heart disease.A strange twist of nature provided the needed clues to thwart the misfolding process, Dr. said. Because transthyretin diseases tend to be more common than usual in Portugal, families there are screened to see who is at risk. One very large family had the mutated gene, he said, yet no one ever got sick.It turned out that a second gene that made the other two subunits in the protein had undergone its own mutation, suppressing or reversing the disease process. Family members carried a cure to an inherited disease within their own genes.By looking at these two subunits, Dr. found that they prevented the misfolding process by erecting a kind of barrier between the normal and abnormal protein states. Proteins fold and unfold under the influence of energy barriers — basically electrical forces inherent to the folding process. When energy barriers are low, as with the mutated subunits, abnormal protein sheets tend to form. When energy barriers are high, as with the protective subunits, it is almost impossible for transthyretin to form abnormal sheets."It's like Mother Nature built a thousand-foot wall between the two protein states," Dr. said.He and his colleagues screened libraries of small molecules to find ones similar to the protective protein subunits. They identified six, all drugs currently approved by the Food and Drug Administration for other uses. Clinical trials are about to begin for the two forms of heart disease caused by misfolded transthyretin, he said.gigi* Researchers Report Promising Treatment for 2 Heart Ailments http://www.nytimes.com/2003/01/30/health/30CND-PROT.html