Researchers from the La Jolla Institute for Allergy & Immunology have joined forces with the Dana-Farber Cancer Institute and Washington University in St. Louis to investigate Lexiscan™ for sickle cell disease. The drug is currently marketed by Astellas Pharma as a pharmacologic stress agent for heart disease diagnosis.
“We will be testing the ability of Lexiscan to reduce inflammation that contributes to the poor blood flow and serious complications characteristic of sickle cell disease,” says La Jolla Institute’s Joel Linden, Ph.D., whose research laid the groundwork for the trial. The study is being funded primarily by a $1.2 million, two-year American Recovery and Reinvestment Act (ARRA) stimulus grant from the National Heart Lung and Blood Institute.
David G. Nathan, M.D., president emeritus of the Dana-Farber Cancer Institute, former physician-in-chief at Children’s Hospital Boston, and co-leader of the project, will direct the clinical component of the trial. Dr. Linden and his team will analyze blood samples from participants, which will be collected from adults at two trial sites: Brigham and Women's Hospital in Boston and Washington University in St. Louis. Pending these results a trial site for children 14 years of age and older is planned at Children’s Hospital Boston in the study’s second year.
Lexiscan is indicated for radionuclide myocardial perfusion imaging. It is used in patients unable to undergo adequate exercise stress testing. The compound is given in 10-second, intravenous doses during coronary stress testing. The new trial will test smaller doses of Lexiscan, administered for longer periods of time to potentially suppress inflammation.
Dr. Linden has been researching the effects of adenosine, a signaling molecule similar to the active ingredient in Lexiscan, in mouse models of sickle cell disease for the last four years. He explains that adenosine binds to receptors known to be important in blocking inflammation. In his studies, Dr. Linden found that adenosine significantly reduced inflammation and pulmonary defects in the sickle cell mice.
He also pinpointed the specific white blood cells causing the inflammation, known as invariant natural killer T cells or iNKT cells. Dr. Linden, working in conjunction with Joshua Field, M.D., a hematologist from Washington University, found that patients with sickle-cell disease have significantly elevated numbers of activated iNKT cells. “This further validated that inflammation plays a major role in this disease,” he said.
In sickle cell disease, also known as sickle cell anemia, the body’s oxygen-carrying red blood cells become stiff, sticky, and misshapen or sickled in appearance and clog the body’s small blood vessels. This leads to reduced blood flow and lower oxygen levels, causing symptoms such as anemia, pain crises, organ damage, or even death. Inflammation caused by white blood cells of the immune system has been shown to significantly exacerbate sickle cell disease.
The trial will begin in adults with sickle cell disease but no painful crises, giving different test doses of Lexiscan for periods of 12 and 24 hours to ensure that it does not cause toxicity. Pending these results, the team will then move to test Lexiscan in adults with pain crises and acute chest syndrome, and, in the second year, in children age 14 and older.