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Repurposed anti-cholesterol drug could improve treatment-resistant anemias

Each year, between 25 and 35 children in the United States and Canada are diagnosed with an inherited bone marrow failure syndrome called Diamond Blackfan anemia (DBA), according to the US Centers for Disease Control and Prevention. Although rare, this syndrome causes a deficiency in producing that is devastating for patients and their families. The only treatment, other than blood transfusions, is glucocorticoids — steroids that cause unwanted and even dangerous side effects, including stunted growth, osteoporosis, cataracts, and glaucoma.

Whitehead Institute Founding Member first took an interest in DBA back in 2007 at a small meeting of researchers and patient families. When he learned that there was no clear understanding of why glucocorticoids seemed to help DBA patients, he decided to devote a portion of his lab’s efforts to solving this mystery.

“We’re not only trying to understand how to treat a rare disease, but we’re also trying to understand a basic biological problem, which is how stem cells and certain other types of cells make a decision when they divide,” says Lodish, who is also Professor of Biology and Professor of Biological Engineering at MIT. “What kind of cell does a blood- forming stem cell become, a stem cell like its parent, or a cell that begins the process of differentiation towards forming a or a white blood cell?”

Now research in Lodish’s lab has identified a cell receptor that, when stimulated by a currently approved cholesterol-lowering drug, and used in combination with low amounts of glucocorticoids, causes a three- to five-fold increase in red blood cell production. The research, which is described online this week in the journal Nature, is serving as the foundation for an upcoming clinical trial.

Unlike some anemias, DBA cannot be treated by erythropoietin (EPO), a hormone that controls red blood cell production by causing red blood cell progenitors, called colony forming unit-erythroids (CFU-Es), to divide and differentiate into red blood cells. In DBA, the CFU-Es die before they can make red blood cells, and patients have too few CFU-Es to make EPO treatment effective.

In 2010, Lodish and his lab determined that glucocorticoids increase red blood cells in EPO-resistant anemias, including DBA, by acting on burst-forming unit-erythroids (BFU-Es), which are cells that, when they divide, can produce multiple CFU-Es. Glucocorticoids increase the likelihood that when BFU-Es divide, one or both of the resulting cells remains a BFU-E instead of differentiating into CFU-Es. Patients treated with glucocorticoids have more BFU-Es, which in turn produce more CFU-Es and, ultimately, more red blood cells.