Clinical
Hemoglobinopathies
Overview
Hemoglobinopathies are inherited genetic disorders in which either the quality or quantity of hemoglobin is abnormal. The hemoglobinopathies, sickle cell anemia and thalassemia, are the two most common inherited genetic disorders in the world affecting several million people worldwide. Sickle cell anemia is caused by the synthesis of an abnormal type of hemoglobin, hemoglobin S, while thalassemia is characterized by genetic defects that lead to reduced levels of synthesis of individual globin chains. In some patients, these two illnesses occur together leading to various combined sickle cell thalassemic disorders. At present, there are limited therapeutic options available for patients suffering from hemoglobinopathies so that there is a strong need for developing new therapies for these chronic and debilitating illnesses.
Sickle Cell Anemia
Sickle hemoglobin (hemoglobin S) is characterized by a mutant type of hemoglobin in which there is a single amino acid substitution (glutamic acid to valine) at position 6 of the beta globin chains. Sickle cell anemia occurs when a patient inherits a sickle globin gene from both of their parents and thus is a homozygous recessive disorder. There are several million people worldwide who suffer from sickle cell anemia. There are over 1,000 new patients born each year and approximately 80,000 patients currently suffer from this disease in the United States. The disease afflicts a similar number of patients in Europe.
Anemia is caused by significantly reduced survival of RBCs containing hemoglobin S. Although anemia can be severe, it is the sickling of RBCs that is responsible for most of the disease's clinical manifestations. Unlike normal RBCs, which are normally biconcave discs that are easily deformable and squeeze through organs to deliver oxygen to tissues and return to the lungs, sickled RBCs become rigid and cannot squeeze through small blood vessels. Instead, they stack up and occlude blood flow, which deprives organs and peripheral tissues of oxygen-carrying blood. It is this process that results in the periodic episodes of pain and vital organ damage, which result in: acute crises (characterized by severe bone, abdominal and chest pain); infections; strokes; pulmonary hypertension leading to heart failure; bone damage leading to arthritis and fractures; kidney failure; leg ulcers; and iron overload (damaging heart, liver and endocrine organs) from transfusion therapy. Nearly half of patients with sickle anemia die by the age of 40 years old in the United States today, which makes it a leading cause of early death.
Stroke, cardiopulmonary disease and kidney failure are leading causes of morbidity and mortality in sickle cell anemia patients. Hospitalizations are frequent to treat crises as well as organ failure caused by the disease. In the United States, over 60,000 hospitalizations take place in sickle cell anemia patients each year. According to a 1991 study, each episode resulted in $22,000 in total hospital costs. In a 2004 study, over $500M in direct hospital costs were attributed to sickle cell anemia patients, which did not include additional costs related to emergency room visits, diagnostic tests, surgery, professional fees and medications. Today, over $5B in total annual costs are incurred related to sickle cell anemia in the United States.
Therapeutic approaches today for sickle cell anemia are largely supportive and designed to prevent or treat complications of the disease, rather than treat the anemia itself. Many patients end up on chronic transfusion therapy to reduce their risks of strokes. Pain medication is required to treat the frequent occurrence of painful crises. Bone marrow transplantation is effective, but rarely used due to the risks and need for matched donors. More recently, hydroxyurea, which was originally developed as a cancer drug, has been used to increase hemoglobin F levels in order to reduce the sickling of RBCs. Although demonstrating therapeutic activity in some patients, the drug has several drawbacks, which have limited its widespread use.
Beta Thalassemia
Thalassemia is actually a group of disorders defined by a reduced rate of synthesis of one or more globin chains. There are thought to be more than two million thalassemic patients in the world with the disease being most common in India, the Middle East and Southeast Asia. Beta thalassemia is also common in Europe, especially in certain Mediterranean countries such as Italy, where there are over 7,000 patients and Greece, where thousands of patients are known to have the disease. Today, there are 1,100 patients suffering from beta thalassemia in the United States and the numbers are rising, because the vast majority of immigrants are coming from regions with high rates of thalassemia.
Beta thalassemia is the most common and serious type of thalassemia. In healthy individuals, hemoglobin, the oxygen-carrying blood protein, is made up of two pairs of peptides, known as alpha and beta chains. In beta thalassemia, the production of beta globin chains is significantly reduced, which results in excess alpha chains in the patients' RBCs. The excess alpha chains tend to precipitate, which results in premature death of both RBCs and their precursors, causing severe anemia. Ineffective erythropoiesis (RBC production) also leads to massive expansion of bone marrow causing severe bony abnormalities in patients with thalassemia. Patients have a propensity to store iron despite their anemic condition. This along with chronic transfusion therapy leads to iron overload, which results in damage to vital organs such as the heart, liver and endocrine organs. Patients frequently develop cardiac arrhythmias and heart failure as well as a range of endocrine disorders, such as diabetes and hypothyroidism. The average age at death of thalassemia patients is 27 years old in the United States.
Transfusion remains the most effective therapy for patients with severe forms of thalassemia. Aggressive transfusion therapy to maintain the hemoglobin levels above 8-10 g/dl can reduce many of the long-term complications that are related to the disease. Iron overload is treated with iron chelation therapy, which is effective, but expensive (more than $30,000 per year) and associated with side effects that have limited its use. The average annual cost for treating adult patients with thalassemia is well over $100,000 in the United States. Thus, despite the relatively small number of patients, several hundred million dollars in total costs are related to thalassemia patients in the United States each year. Marrow or stem cell transplantation is effective but rarely used due to its risks and the need for matched tissue donors.
New Therapeutic Approach: Fetal Globin Gene Induction
Hemoglobinopathies are particularly challenging diseases, because the illness is caused not only by inadequate production of healthy RBCs, but the production of abnormal hemoglobins that lead to illness. In sickle cell anemia, the mutant beta chain combines with normal alpha chains to form the characteristic hemoglobin S molecules that aggregate together to form sickled RBCs. In thalassemia, there is an excess of alpha globin chains, which aggregate and destroy RBCs. There has been a strong interest in finding ways to produce globin chains that can substitute for the absent and defective beta chains characteristic of thalassemia and sickle cell anemia, respectively.
Normally, hemoglobin is made up of a pair of alpha chains and non-alpha chains. Alpha chains begin to be synthesized early in fetal development. During most of fetal development, gamma chains known as fetal globin chains are the predominant form of non-alpha chains. These chains combine with alpha globin chains to produce fetal hemoglobin (hemoglobin F). Late in fetal development adult hemoglobin is formed when beta chains begin to be synthesized and combine with alpha chains to form normal adult hemoglobin. Adults normally have predominantly adult hemoglobin, but still have small, but detectable levels of fetal hemoglobin in their RBCs.
Fetal globin has the therapeutic potential to correct the RBC defects and reverse the pathophysiology of both sickle cell anemia and beta thalassemia, because:
- Fetal and adult hemoglobin have similar structure and identical oxygen-carrying capacity.
- Adult erythroid bone marrow cells still contain fetal globin genes (even though the production of fetal globin chains is suppressed after birth).
- Fetal globin genes can be turned back on (re-activated) to produce fetal globin, which prevents RBC sickling and death.
- Sickle cell anemia and thalassemia patients with higher levels of hemoglobin F in their RBCs have mild disease and better clinical outcomes.
- High levels of hemoglobin F are safe in patients.
Hydroxyurea
Hydroxyurea is the only therapeutic agent currently approved by the FDA to treat the underlying pathology of sickle cell anemia. However, hydroxyurea is only active in a subset of patients and is not approved for treating thalassemia. It increases hemoglobin F levels and has demonstrated therapeutic effects in about 40-50% of sickle cell anemia patients. However, it is a powerful cancer chemotherapy drug that has many risks due to its mutagenic and anti-proliferative properties. These properties can increase risks of cancer and fetal abnormalities as well as lower blood counts in patients on the long-term treatment required for sickle cell anemia patients. Because of its limitations and the lack of other approved drugs to treat sickle cell anemia or any approved drugs to treat thalassemia, there is a strong need for newer agents that are safer and potentially more effective to treat sickle cell anemia and are also effective in treating thalassemia.