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Could an old antidepressant treat sickle cell disease?
Date:2/19/2013

p>"This is the first time that fetal hemoglobin synthesis was re-activated both in human blood cells and in mice to such a high level using a drug, and it demonstrates that once you understand the basic biological mechanism underlying a disease, you can develop drugs to treat it," says Doug Engel, Ph.D., senior author of the study and chair of U-M's Department of Cell & Developmental Biology. "This grew out of an effort to discover the details of how hemoglobin is made during development, not with an immediate focus on curing sickle cell anemia, but just toward understanding it."

Engel credits the dedication and persistence of his team, including a former research assistant professor, Osamu Tanabe, M.D., Ph.D., now at Japan's Tohoku University, U-M postdoctoral fellow, Lihong Shi, Ph.D., first author of the study, and research instructor Shuaiying Cui, Ph.D..

Together, they have identified LSD1's crucial role, and its epigenetic interaction with two nuclear receptors in the nuclei of red blood cell precursors called TR2 and TR4. Working in tandem, they repress the expression of the gene that makes fetal hemoglobin an effect called gene silencing. So, interfering with this repression allows the fetal hemoglobin subunits to be made.

Treatment with TCP caused fetal hemoglobin to be produced at such high abundance that it made up 30 percent of all hemoglobin in cultured human blood cells a finding Engel called "startling." TCP is FDA-approved, though patients taking it need to follow strict dietary guidelines to avoid drug interactions with certain naturally occurring chemicals in some foods.

Boosting healthy hemoglobin

Sickle cell disease occurs when a person or animal inherits two defective copies of a gene that governs the production of the "adult" form of hemoglobin. James Neel, the first chair of the U-M Department of Human Genetics, co-discovered the genetic basis for the disease in the late 1940s.

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Contact: Kara Gavin
kegavin@umich.edu
734-764-2220
University of Michigan Health System
Source:Eurekalert  

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