Sickle cell disease and bone marrow transplantation #ASH09

Sickle cell disease, a condition characterized by deformed and dysfunctional red blood cells, is one of the most common genetic blood disorders affecting millions of people around the world, including more than 70,000 Americans. Research presented today at the 51st Annual Meeting of the American Society of Hematology highlights intriguing studies on the acute danger that the H1N1 pandemic presents for children with this blood disorder, evaluations of both new and standard treatments for common complications of sickle cell disease, and an expansion of the current understanding of hemoglobin expression in red blood cells that may lead to new treatments.

“Treatment for sickle cell disease consists primarily of life-long supportive care, with the only cure being bone marrow transplantation – a risky procedure that is not readily available for most patients,” said Alexis Thompson, MD, PhD, moderator of the press conference and Hematology Section Head at the Children’s Memorial Hospital and Associate Professor of Pediatrics, at Northwestern University Feinberg School of Medicine, Chicago. “Therefore, research in this area is particularly important to help ensure that improved therapies continue to be developed and that patients with sickle cell disease have access to the best possible care.

As infants develop in the womb, the gamma-globin gene produces a fetal form of hemoglobin, the protein inside red blood cells that carries oxygen. Shortly after birth, a switch to beta-globin gene expression normally occurs, which leads to the production of adult hemoglobin. Both fetal and adult hemoglobin function similarly, though fetal hemoglobin has a greater affinity for binding with oxygen.

Patients with sickle cell disease have a defective form of adult hemoglobin that causes their red blood cells to become deformed and sickle shaped. As a result, the cells are unable to efficiently carry oxygen to the body’s tissues and often stick together and jam vessels, causing blood flow obstruction and episodes of severe pain. If a patient with sickle cell could continue production of the fetal hemoglobin and produce less of their defective adult sickle hemoglobin, many of their complications could possibly be reduced or eliminated. A team of researchers from Harvard Medical School in Boston studied the therapeutic possibility of turning the genetic “switch” back on for the production of fetal hemoglobin to replace the defective adult hemoglobin and alleviate these devastating symptoms.

In previous studies, a gene called BCL11A was found to be involved in blocking the expression of fetal hemoglobin in adults. To test these findings in vivo and investigate the role of BCL11A in hemoglobin regulation at different developmental stages, the researchers performed genetic tests in both embryonic and adult mice that were genetically engineered to carry a complete human beta-globin gene cluster capable of producing adult hemoglobin.

In the embryonic mice, inactivation of the BCL11A gene led to a robust expression of gamma-globin (the fetal form of hemoglobin) during late gestation: more than 90 percent of the globin produced was of this type. Tissue-specific deletion of the BCL11A gene in the adult mice (8-10 weeks old) resulted in an increase of more than 1,000-fold in gamma-globin gene expression in the bone marrow erythroblasts (the precursors to red blood cells) of the experimental mice in comparison to control mice. This increase in the gamma-globin expression after inactivation of BCL11A was rapid and persisted during the course of the experiments (up until the mice were 25 weeks old). 

 “Currently, there are only a limited number of therapies available for patients with sickle cell disease and thalassemia, another disorder involving abnormal hemoglobin,” said senior study author Stuart H. Orkin, MD, David G. Nathan Professor of Pediatrics at Dana-Farber Cancer Institute, Children’s Hospital Boston, and Harvard Medical School in Boston. “This research opens up a new avenue for treatment, a way to genetically activate healthy fetal hemoglobin in the red blood cells of patients with these lifelong blood disorders.”