Hemoglobin molecules are contained in red blood cells and are responsible for carrying oxygen to the body's tissues and organs. Hemoglobin consists of two alpha and two beta peptide globin chains. The two most common hemoglobin disorders are due to either a mutation in the beta globin gene resulting in abnormal beta globin chains, which causes sickle cell disease, or decreased production of beta globin chains, which causes beta thalassemia. These hemoglobin disorders are the most common inherited genetic disorders and afflict several million patients worldwide. At present, there are limited therapeutic options available for patients suffering from these hemoglobin disorders. There is a strong need for developing new therapies for these chronic and debilitating illnesses.
Sickle Cell Disease
Sickle hemoglobin (hemoglobin S) is a mutant type of hemoglobin in which there is a single amino acid substitution in the beta globin chains. In the United States, there are over 1,500 new patients born each year, and approximately 100,000 patients currently suffer from this disease. Anemia is caused by significantly reduced survival of red blood cells containing hemoglobin S. Although anemia can be severe, it is the sickling of red blood cells that is responsible for most of the disease's clinical manifestations. Sickled red blood cells (picture to the left) become rigid and cannot pass through small blood vessels, where they stack up and block blood flow to organs and tissues of the body. This process results in the periodic episodes of pain and vital organ damage, which result in repeated acute pain crises, lung damage (acute chest syndrome), strokes, and infections. Over time, chronic damage can occur in the lungs, kidneys and other organs. Joint damage and skin ulcers are common findings. Patients with sickle cell disease usually have shortened survival.
Therapeutic approaches for sickle cell disease are largely supportive and designed to prevent or treat complications of the illness, rather than treat the underlying disease process. Many patients require repeated transfusions to reduce the risks of recurrent strokes. Pain medication is required to treat the frequent painful crises. Bone marrow transplantation is effective, but rarely used due to a paucity of matched donors. Hydroxyurea, a cancer drug, is approved by the FDA to decrease the frequency of sickle cell disease crisis, primarily by increasing fetal hemoglobin levels. The drug shows therapeutic activity in about half of patients. However, its use has been limited due to its mutagenic risks as well as its suppressive effects on blood production requiring frequent patient monitoring. More therapies are needed.
Thalassemias are the most common type of genetic disorder in the world. Beta thalassemia is found in Mediterranean regions, India and Pakistan, the Middle East, Southeast Asia and South America. With immigration, this disease is becoming more common in the United States. In beta thalassemia, production of beta globin chains is significantly reduced, which results in excess alpha chains in red blood cells. The excess alpha chains are toxic and cause premature death of red blood cell precursors, resulting in severe anemia. Patients have increased iron absorption, which, with chronic transfusion therapy, leads to iron overload and damages vital organs, including the heart, liver, and endocrine organs. Patients frequently develop cardiac arrhythmias and heart failure. Currently, the average age at death of thalassemia patients is just 27 years old in the United States.
Transfusion remains the most effective therapy for patients with severe forms of thalassemia, but is associated with risk of transmission of infectious agents, iron overload, and other complications. Iron overload is treated with iron chelation therapy, which is effective, but expensive ($30,000-$70,000 per year) and associated with side effects. Marrow or stem cell transplantation is curative, but has significant risks and requires closely matched donors. There are no FDA-approved therapies to treat the underlying disease.