Transthyretin (TTR) related cardiac amyloidosis is a progressive infiltrative cardiomyopathy that mimics hypertensive, hypertrophic heart disease and often goes undiagnosed. In the United States, the hereditary form disproportionately afflicts Blacks, who when compared to Whites with wild type TTR amyloidosis, a phenotypically similar condition, present with more advanced disease despite having a non-invasive method for early identification (genetic testing). While reasons for this are unclear, this begs to consider the inadequate access to care, societal factors or a biological basis.
So, what are scientists and doctors doing to prevent this?
When folded the right way, proteins in the body perform their jobs as efficiently as any well-designed factory machine. Folded the wrong way, disease can strike.
Scientists in California have found a way to prevent proteins from misfolding and thereby potentially prevent or at least arrest any one of hundreds of “amyloid” diseases. The study was done in a laboratory setting, but tests on humans are underway.
“Ideally, if you knew who was at risk for the disease, you would
administer drugs prophylactically,” says Jeff Kelly, senior author of the study appearing in the issue of Science. “There’s reason to believe that they could be useful after the disease manifests itself clinically. I’m really optimistic that this will be useful no matter how you do it – as long as you do it, as long as people get treated.”
Amyloid diseases, which include multiple myeloma, rheumatoid arthritis, Crohn’s disease, ulcerative colitis, transthyretin, cutaneous, Alzheimer’s, Parkinson’s, cystic fibrosis and mad cow disease, result when misfolded proteins amass to form amyloids, which are plaque-like structures that crowd different organs in the body.
Much research has focused on dealing with the amyloids once they are formed. The authors of this study intervened a step earlier.
Under normal conditions, proteins fold themselves into three-dimensional structures that then perform work much like screws and bolts, says Marc Gillespie, a professor of pharmaceutical sciences at St. John’s University in Queens, N.Y. How exactly proteins acquire their specific shape, has been a bit of a mystery. “It’s the equivalent of taking a string of pearls and getting a steering wheel out of it,” Gillespie says.
The authors of this study looked at a case of a protein gone awry: transthyretin amyloid diseases, which involve misfolding of the protein transthyretin (TTR). TTR is secreted by the liver into the bloodstream, where it acts as a transporter for thyroid hormone and vitamin A.
Normal TTR is composed of four identical copies of the protein that bind to each other. Certain genetic defects, however, cause this structure (called a tetramer) to come apart easily, giving the parts the chance to change shape, misfold, and come back together into the dreaded amyloid fibrils.
The researchers designed small
molecules that bind to the TTR and provide a stabilizing influence by requiring more energy to break it up.
The authors feel the strategy could work on the myriad of other amyloid diseases, although others are not so sure.
“I think there are some real complications when we try to extend this to Alzheimer’s,” says Bill Thies, vice president for medical and scientific affairs for the Alzheimer’s Association. “It’s not clear whether it’s the accumulated amyloid that is the toxic species in Alzheimer’s disease, so there’s no way of knowing whether interfering with folding would be a useful technique.”
It’s also not clear that compounds that work in one part of the body would also be able to penetrate the blood-brain barrier. “If we are going to impact amyloid folding in the brain, then we are going to have to get into the brain,” Thies says.
Kelly, however, feels it’s doable. And more results may appear sooner than people think. Some of the compounds used in the Science paper are known drugs and are also known to be safe. They are now being tested for efficacy.
For more information on heart health and heart failure, visit our Health Conditions page on BlackDoctor.org.
SOURCES: Jeff Kelly, Ph.D., vice president, academic affairs, Scripps Research Institute, La Jolla, Calif.; Bill Thies, Ph.D., vice president, medical and scientific affairs, Alzheimer’s Association, Chicago; Marc Gillespie, Ph.D., professor, pharmaceutical sciences, St. John’s University, Queens, N.Y.; Jan. 31, 2003, Science
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