Thalassemia is a heterogeneous group of inherited blood disorders arising from defects in the genes that encode the two forms of hemoglobin (alpha and beta), resulting in improper oxygen transport and destruction of red blood cells in a patient.
Hemoglobin is the molecule in red blood cells that carries oxygen from the lungs to the body’s tissues and returns carbon dioxide from the tissues back to the lungs. Hemoglobin is a four-subunit protein complex formed of two α-subunits and two β-subunits, each with an iron-containing heme group that binds to, and carries oxygen molecules within, red blood cells. Due to spontaneous mutation, hemoglobin gene variants are present to a low degree in all populations. Although most gene variants are rare and many are harmless, certain mutations result in severe hemoglobin disorders.
The most common severe hemoglobin disorder is related to mutations in the β-subunits and is thus termed β-thalassemia. If both genes are affected, symptoms are much more severe and the disease is then referred to as β-thalassemia major.
The defects in the genes result in ineffective formation of red blood cells and damage to existing red blood cells. As a result, β-thalassemia major patients typically present with life-threatening anemia within the first year of life and if left untreated will have a life expectancy of no more than three years. Other symptoms include jaundice, enlarged organs, misshapen bones and stunted growth.
There is currently no approved curative treatment for β-thalassemia major. Its main symptom, anemia, is treated through regular and lifelong red blood cell transfusions, which are generally needed every two to four weeks. However, this frequently leads to iron overload, which is the principal cause of mortality in β-thalassemia major patients. To control iron overload, iron chelation therapy is required as the standard treatment in these patients and typically begins after patients have received approximately twenty transfusions during their lifetime.
The course of the disease depends largely on whether patients are maintained on an adequate transfusion and iron chelation regime. Poor compliance with transfusion or iron chelation is associated with a poor prognosis and shortened survival. However, even with the standard of care, patients are at risk of infection from transfusions as well as toxicities related to iron chelation therapy.
Given the reduction in quality of life, morbidity and mortality in combination with the significant healthcare burden, there is need for a curative treatment for the disorder.