Older Antidepressant Drug May Prove Beneficial for Treating Sickle Cell Disease

The discovery may also lead to other treatments for the disease, which leads malformed red blood cells to cause vascular injury and premature death.

However, the researchers warn it is too soon for the agent to be used in routine treatment of sickle cell anemia. In the new article, the researchers describe a meticulous effort to assess TCP’s effect on the body’s production of a particular form of hemoglobin—the key protein that allows red blood cells to carry oxygen. The drug acts on a molecule inside red blood cells called LSD1, which is involved in blocking the production of the fetal form of hemoglobin. The U-M team narrowed in on the significance of LSD1 as a drug target after many decades of research. Then, they simply did a Web search to find drugs that act on LSD1. That is how they discovered TCP, which since 1960 has been used to treat severe depression.

In the new article, the scientists described how TCP suppressed LSD1 and enhanced the production of fetal hemoglobin—offsetting the debilitating impact of the abnormal “adult” form of hemoglobin that sickle cell patients produce. “This is the first time that fetal hemoglobin synthesis was reactivated 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,” stated Doug Engel, PhD, senior author of the study and chair of U-M’s department of cell and 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.”

The scientists have identified LSD1’s vital role, and its epigenetic interaction with two nuclear receptors in the nuclei of red blood cell precursors called TR2 and TR4. Working together, they repress the expression of the gene that makes fetal hemoglobin—an effect called gene silencing. Thus, intervening with this repression allows the fetal hemoglobin subunits to be generated.

TCP treatment caused fetal hemoglobin to be produced at such high amounts that it comprised 30% of all hemoglobin in cultured human blood cells—a finding Dr. Engel called “startling.” TCP is US Food and Drug Administration (FDA)-approved, though patients taking it need to follow strict dietary guidelines to avoid drug interactions with certain naturally occurring chemicals in some foods.

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, codiscovered the genetic basis for the disease in the late 1940s. Individuals with just one copy of the mutated gene normally do not get sick, but if they have a child with another person who carries the same trait, there is a one in four chance the child will develop the disease.

In sickle cell disease, the body makes a form of adult hemoglobin that can amass to cause red blood cells to become C-shaped or “sickle” shaped, and stiff and tacky. Those cells clog small blood vessels in the limbs and internal organs, causing organ damage, pain, and raising the risk of infection. Life expectancy in these patients is greatly shortened.

In a very small number of sickle cell patients, the “fetal” form of hemoglobin, which is commonly only made in the womb and the first couple of months of life, keeps being produced throughout life. These patients have symptoms that are either far less severe or nonexistent.

The most typical current sickle cell treatment, oral hydroxyurea, tries to increase fetal hemoglobin production. Others, including stem cell (bone marrow) transplants and transfusions from unrelated donors, aim to exchange the source of the overall red blood cell supply.

Andrew Campbell, MD, who directs the U-M’s Pediatric Comprehensive Sickle Cell program at U-M’s CS Mott Children’s Hospital and has worked with Dr. Engel on earlier studies, found the new findings are very exciting news for sickle cell patients, since there are not enough treatment alternatives. However, he noted, more clinical research is required to determine if the findings from mice and cultured human red cell precursors will convert to humans for TCP or even other drugs that inactivate LSD1.

The first such clinical trial is now being planned with the sickle cell team at Wayne State University (Detroit, MI, USA). Additional data will be available later in 2013 if it receives approval to go forward. At the same time, U-M is looking into other possible drug candidates targeting the same pathway.

Dr. Engel is working with U-M psychiatrist Juan Lopez, MD, to examine the effect of TCP—and other antidepressants in the class known as monoamine oxidase inhibitors—on hemoglobin production in adults. The study is still seeking volunteers who are already taking these drugs to treat major depression.

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