Two recent studies provide insights into the molecular biology of three blood disorders, which may lead to innovative new approaches to treat these diseases.
The two new studies—one published online March 17, 2013, in the journal Nature Medicine
and the other March 25, 2013, in the online edition of the Journal of Clinical Investigation
—propose two new treatments for beta-thalassemia, a blood disorder that affects thousands of people globally yearly. Moreover, they suggest a new strategy to treat thousands of Caucasians of Northern European ancestry diagnosed with HFE (hemochromatosis gene)-related hemochromatosis and a fresh approach to the treatment of the rare blood disorder polycythemia vera.
These research insights were only possible because two teams of investigators, which included 24 scientists at six American and European institutions decoded the body’s excellent regulation of iron, as well as its factory-like production of red blood cells. “When you tease apart the mechanisms leading to these serious disorders, you find elegant ways to manipulate the system,” stated Dr. Stefano Rivella, associate professor of genetic medicine in pediatrics at Weill Cornell Medical College (New York, NY, USA).
For example, according to Dr. Rivella, two different gene mutations lead to different outcomes. In beta-thalassemia, patients suffer from anemia and, as a consequence, iron overload. In HFE-related hemochromatosis, patients suffer of iron overload. However, he added, one treatment strategy that regulates the body’s use of iron may work for both disorders. Furthermore, investigators found another approach, based on modifying red blood cell production, could also possibly treat beta-thalassemia as well as a very different disorder, polycythemia vera.
In the Nature Medicine study, Dr. Rivella and his colleagues confronted erythropoiesis—the process by which red blood cells are produced—as a means to decipher and decode the two blood disorders beta-thalassemia and polycythemia vera. Beta-thalassemia, a group of inherited blood disorders, is caused by a defect in the beta globin gene. This results in production of red blood cells that have too much iron, which can be toxic, resulting in the destruction of many of the blood cells. What are left are too few blood cells, which leads to anemia. At the same time, the excess iron from destroyed blood cells accumulated in the body, leading to organ damage.
In animal research, the investigators that detaching macrophages from the erythroblasts not only reduced the number of blood cell factories, but also improved anemia. The discovery could be translated into an experimental therapy by finding the molecule that physically binds a macrophage to an erythroblast, and then targeting and inhibiting it. “We need macrophages for good health, but it may be possible to decouple the macrophages that contribute to blood disorders,” Dr. Rivella stated. “I estimate that up 30%–40% of the beta-thalassemia population could benefit from this treatment strategy.”
In the Journal of Clinical Investigation study, researchers from Weill Cornell and from Isis Pharmaceuticals (Carlsbad, CA, USA; www.isispharm.com) examined the body’s exquisite regulation of iron. Too little iron causes anemia. Too much iron in the body results in organ toxicity such as heart attacks and liver failure. Beta-thalassemia and hemochromatosis are two disorders in which affected individuals accumulate too much iron in their bodies.
Now, Dr. Rivella, with his partners at Isis Pharmaceuticals Dr. Brett P. Monia and Dr. Shuling Guo, have revealed the ballet of molecules that controls iron absorption, as well as what goes wrong and how to potentially correct the deficit. Iron control is mostly regulated by hepcidin (Hamp), a hormone secreted into the bloodstream by the liver. Hamp controls the so-called “iron gate” in the intestines, a protein known as ferroportin. Ferroportin allows the body to absorb iron from food to help make red blood cells. If iron levels are too high from iron-rich foods that are eaten, Hamp levels rise, which blocks ferroportin’s iron gate, blocking iron absorption, according to Weill Cornell’s Dr. Carla Casu, a postdoctoral researcher in Dr. Rivella’s laboratory and one of the two lead authors of this study with Dr. Guo at Isis Pharmaceuticals.
Patients with beta-thalassemia and hemochromatosis have levels of Hamp that are too low, so the body absorbs more iron than is healthy. Hemochromatosis occurs because of a deficit in the HFE gene that controls the Hamp hormone. “Hamp is sleeping. It doesn’t wake up when iron comes along, so too much iron is absorbed,” said Dr. Rivella. The defect in beta-thalassemia is due to a defect in the globin gene that helps produce hemoglobin. Therefore, Hamp is shut down because the body senses the anemia, and believes that more iron is required to make red cells. As a result, there is iron overload.”
The researchers discovered the iron overload in both diseases by studying a third disease, a childhood disorder in which a mutation in a gene called Tmprss6 causes Hamp levels to rise too high, so not enough iron is being extracted from the diet. Tmprss6 keeps Hamp levels high during childhood and adolescence, so a body cannot use iron successfully to grow. They reasoned that if they could create the conditions of Tmprss6 mutation—high levels of Hamp hormone and repression of the body’s use of iron—in patients with thalassemia and hemochromatosis, they could treat those disorders. “If we block Tmprss6, we increase the expression of Hamp to normal levels, with the consequence that iron does not now accumulate,” Dr. Monia said.
The research team leaders, Dr. Monia and Dr. Guo from Isis Pharmaceuticals, devised an antisense drug that blocked Tmprss6 “in order to wake up Hamp expression.” An antisense drug works by administering a chemically modified, stable DNA-like molecule that targets specifically an RNA sequence that is generated by the gene. This sequence binds to the natural gene RNA product, forming a double-stranded RNA/DNA hybrid duplex. This duplex is recognized by enzymes in the cell that cause degradation of the natural RNA. “When you destroy that RNA, you destroy the ability of the Tmprss6 to make any protein,” Dr. Monia explained.
Both prospective therapies provide new sways to treat older blood disorder diseases. The researchers, however, need more studies before these therapies can be applied in the clinic, although the antisense technology can be quickly refined for its applications in humans, Dr. Rivella concluded. “These studies are like putting together pieces of a complicated puzzle, which then offers you the big picture, as well as ways to creatively improve the view.”
Weill Cornell Medical College