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The classic view of sickle-cell disease is mechanical: Small blood vessels become clogged with misshapen red blood cells, causing pain and eventual organ damage. However, more than a decade ago, Orah S. Platt, MD, chief of Laboratory Medicine at Children's Hospital Boston, proposed that inflammation caused by leukocytes is an important contributing factor. It's now known that vessel blockage sparks an inflammatory response that greatly exacerbates sickle-cell pain crises and also, in a vicious cycle, exacerbates the sickling itself.
Now, a multicenter clinical trial is exploring whether a drug used in cardiovascular stress testing, Lexiscan®, could ease that inflammation and reduce sickle-cell symptoms, particularly pain and acute chest syndrome. David G. Nathan, MD, former physician-in-chief at Children's and president emeritus of Dana-Farber Cancer Institute, will direct the trial's clinical component.
Safety testing has begun in adults with sickle-cell disease (but no recent pain crises) at Brigham and Women's Hospital and Washington University in St. Louis. If all goes well, the team will move quickly to test small doses of Lexiscan in adults with pain crises and acute chest syndrome, and, in the second year, in children age 14 and older. Matthew M. Heeney, MD, clinical director of the Sickle Cell Program at Children's, will lead the pediatric portion of the trial.
Nathan's primary co-investigator, Joel Linden, PhD, at the La Jolla Institute for Allergy & Immunology, laid the trial's scientific groundwork. Dr. Linden had shown that adenosine, a cellular signaling molecule similar to Lexiscan's active ingredient, significantly reduces inflammation and pulmonary defects in mouse models of sickle-cell disease. With the help of a hematologist from Washington University, he also pinpointed a rare group of white blood cells—invariant natural killer T cells (iNKT cells)—as responsible for the inflammation.
The collaboration, aided by a $1.2 million stimulus grant from the National Heart, Lung, and Blood Institute, began serendipitously. Dr. Nathan, hearing about adenosine at a cancer conference, wondered if it might reduce inflammation in sickle-cell disease. A simple Internet search led him to Dr. Linden.
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