P-Selectin & Sickle Cell
Potential Treatment for Sickle Cell Anemia: P-Selectin Inhibitor
Sickle cell disease affects millions of people throughout the world, particularly black and Hispanic communities. The Centers for Disease Control and Prevention (CDC) estimate that approximately 90,000 to 100,000 Americans have sickle cell disease. Globally, this number is in the millions. Yet there is no widely available cure for the disease. Treatments for sickle cell disease primarily consist of managing the symptoms that come along with the disease, such as pain, anemia and stroke, instead of treating the disease itself.
Healthy red blood cells in the body are typically round and move through small blood vessels to carry oxygen to different parts of the body. In people with sickle cell disease, however, these red blood cells become hard and sticky, taking on a C-shape, also called a “sickle.” The hard and sticky character of sickle cells makes them prone to getting stuck in blood vessels, which in turn clogs blood flow in the body. Once sickle cells are stuck in blood vessels, they can irritate the vascular endothelium, a thin layer of cells lining the inside of blood vessels. As blood flow is obstructed, the irritation caused by sickle cells can also provoke an inflammatory response in the body.
A team of researchers from Emory University led by Richard Cummings, PhD, William Patterson Timmie Professor and Chair of Biochemistry, and Elliot Chaikof, MD, PhD, Johnson and Johnson Professor of Surgery at the Harvard University School of Medicine and the former John E. Skandalakis Chair of Surgery at Emory, has discovered a potential fix to this problem. To block harmful inflammatory responses, the team knew they needed to block the binding of leukocytes, or white blood cells, to endothelial cells, which line blood vessels.
The mechanism involves an interaction between a receptor on a cell and a ligand, a molecule on a cell. When a receptor binds to a matching ligand, the molecule performs an action such as activating a protein. This technology deals specifically with P-selectin, a protein that helps activate leukocytes to invoke an inflammatory response in the body. The ligand for P-selectin is the P-selectin glycoprotein ligand-1, or PSGL-1, which is expressed on the surface membranes of leukocytes. Richard Cummings and his team have set out to prevent an inflammatory response in the body by blocking P-selectin from being activated. In other words, they created a P-selectin inhibitor.
Chaikof explains the science behind it using a “lock and key” metaphor. The P-selectin is a lock, and PSGL-1 ligands are the keys. The PSGL-1 ligands will unlock P-selectin, activating an inflammatory response in the body. Cummings and the team at Emory countered this by creating a “fake” ligand, which would mimic the characteristics of PSGL-1. In effect, the imitation ligand would act as a decoy, preventing any interaction between P-selectin and PSGL-1.
“If you make a false key or a decoy, that decoy is not really attached to a cell,” Chaikof explains. “It just blocks an interaction from taking place and prevents those cells that actually contain that key from hooking into the lock.”
“Inflammation is a common complication of sickle cell disease and only generic anti-inflammatories are currently used to address this inflammatory response. This new innovation targets the root of the problem for the specific inflammatory responses that occur due to sickle cell disease,” says Justin Burns, OTT case manager.
While sickle cell disease is one of the major ways this technology could prove useful, Chaikof says it could also prove useful in treating other conditions, such as blood clots, heart disease and inflammatory bowel disease.
“We think that it’s a very promising drug candidate for a variety of different inflammatory disorders,” Chaikof says.
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This research was published earlier this year in Nature Communications.