Recent Progress in Gene Therapy and Other Targeted Therapeutic Approaches for Beta Thalassemia

摘要

Beta-thalassemia is a genetic disorder characterized by the impaired synthesis of the betaglobinchain of adult hemoglobin. The disorder has a complex pathophysiology that affects multipleorgan systems. The main complications of beta thalassemia are ineffective erythropoiesis, chronic hemolyticanemia and hemosiderosis-induced organ dysfunction. Regular blood transfusions are themain therapy for beta thalassemia major; however, this treatment can cause cardiac and hepatic hemosiderosis– the most common cause of death in these patients. This review focuses on unique futuretherapeutic interventions for thalassemia that reverse splenomegaly, reduce transfusion frequency, decreaseiron toxicity in organs, and correct chronic anemia. The targeted effective protocols includehemoglobin fetal inducers, ineffective erythropoiesis correctors, antioxidants, vitamins, and naturalproducts. Resveratrol is a new herbal therapeutic approach which serves as fetal Hb inducer in betathalassemia. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for beta thalassemiamajor and is preferred over iron chelation and blood transfusion for ensuring long life in thesepatients. Meanwhile, several molecular therapies, such as ActRIIB/IgG1 Fc recombinant protein,have emerged to address complications of beta thalassemia or the adverse effects of current drugs. Regardinggene correction strategies, a phase III trial called HGB-207 (Northstar-2; NCT02906202) isevaluating the efficacy and safety of autologous cell transplantation with LentiGlobin. Advancedgene-editing approaches aim to cut DNA at a targeted site and convert HbF to HbA during infancy,such as the suppression of BCL11A (B cell lymphoma 11A), HPFH (hereditary persistence of fetalhemoglobin) and zinc-finger nucleases. Gene therapy is progressing rapidly, with multiple clinical trialsbeing conducted in many countries and the promise of commercial products to be available in thenear future.