Sickle cell disease is a serious genetic condition that affects red blood cells, causing them to become misshapen and sticky. It affects at least 100,000 people in the U.S., leading to blood clots, painful blockages in blood vessels, and shortened lifespans.
Researchers in the Duke Department of Biochemistry have discovered a key biological pathway that contributes to these complications. Their findings also suggest a promising treatment strategy: blocking a protein that initiates the process using a drug that’s approved for gout treatment in some countries.
Red blood cells affected by sickle cell disease show abnormal levels of a molecule called phosphatidylserine (PS), which signals the body to start clotting and facilitates sickle cells blocking blood vessels. Until now, scientists didn’t fully understand why PS appears in such high amounts.
In a study published in the American Journal of Hematology, Huanghe Yang, PhD, associate professor of biochemistry, and his colleagues uncovered a chain reaction that occurs when sickle cells lose oxygen and change shape. At the center of this process is a protein called PIEZO1, which senses mechanical stress. Once activated, PIEZO1 allows calcium to enter the cell, which then switches on another protein, TMEM16F. This protein moves phosphatidylserine (PS) to the cell’s surface, triggering clotting and blood vessel blockages.
“Our study reveals that mechanical stress from sickling activates PIEZO1, which then triggers TMEM16F to externalize PS,” Yang said.
Working with blood cells from both humans and mice, the researchers showed that benzbromarone — a drug used to treat gout in other countries — can partially block PIEZO1 and reduce these harmful effects. While benzbromarone is not used in the U.S. due to liver toxicity concerns, the study provides a proof of concept that targeting this pathway could be a viable strategy for treating sickle cell disease.
Next, the researchers plan to test benzbromarone in a mouse model of sickle cell disease and work toward developing safer, more selective inhibitors that target PIEZO1 and TMEM16F.
Other authors: Pengfei Liang, Yui-Chun S. Wan, Ke Z. Shan, Ryan Chou, Yang Zhang, Martha Delahunty, Sanjay Khandelwal, Samuel J. Francis, Gowthami M. Arepally, and Marilyn J. Telen.
Funding: The National Institutes of Health, The American Society of Hematology.