Research presented last week at the 24th Congress of European Hematology Association (EHA) in Amsterdam found gene therapy to be effective in treating animal models of thalassemia. By targeting genes associated with iron regulation and erythropoiesis, or the production of red blood cells, they were able to successfully dampen the symptoms of the blood disorder. These findings were presented by Dr. Antonella Nai of the San Raffaele Scientific Institute in Milan, Italy. The Need for Improved Thalassemia Therapies Beta-thalassemia is an inherited disorder that causes impaired erythropoiesis, anemia, excessive iron concentrations, and enlargement of the spleen. It is caused by a mutation in the beta-globin chain of the adult hemoglobin molecule. To manage this disease, patients must undergo lifelong blood transfusions and iron chelation, or removal of excess iron from the blood. Bone marrow transplants have shown success in a few patients with viable donors; however, no treatment has been effective for all patients. Experimental approaches to treating thalassemia include gene therapy and drugs that target abnormal red blood cell production or the iron overload. Background of the Preclinical Trial In their preclinical trial involving a thalassemic mouse model, Nai and colleagues combined these two approaches. To decrease excess iron, they used antisense oligonucleotides (ASOs) specific to the TMPRSS6 gene. This gene’s product is a key regulator of iron balance in the body. The ASO treatment is effective in degrading this TMPRSS6 gene product, allowing iron levels to decrease to a healthy level. Nai noted that a phase I clinical trial has found the deletion of TMPRSS6 to be effective in reducing iron levels as well. The second approach involved use of gene therapy to delete the TFR2 gene in the bone marrow. This gene codes for an erythropoiesis regulator, which plays an important role in the production of red blood cells. Deletion of this gene causes increased erythropoietin sensitivity in the bone marrow cells, which improves red blood cell production. Promising Results of Combined Therapy The researchers found that this combined therapy significantly improved anemia in the mouse model, with red blood cell and hemoglobin concentrations increasing. They note that by having a beneficial effect on the thalassemic phenotype, this treatment creates possibilities for new drugs to target different mechanisms of the disease. When asked if she felt gene therapies could eventually be applicable to all patients, Nai noted that though the treatment is very promising, it comes at a high cost. In addition to the expenses associated with gene therapy, Nai also claimed that data has shown more promise for younger patients than in older adults, being that living long-term with a genetic condition can bring about other complications. She concluded that gene therapy has great potential, and that a combination of gene and pharmaceutical therapy may be best fit for patients who do not respond to the former. Source
