title: Gene therapy for hemoglobinopathies: progress and challenges.
abstract: Hemoglobinopathies are genetic inherited conditions that originate from the lack or malfunction of the hemoglobin (Hb) protein. Sickle cell disease (SCD) and thalassemia are the most common forms of these conditions. The severe anemia combined with complications that arise in the most affected patients raises the necessity for a cure to restore hemoglobin function. The current routine therapies for these conditions, namely transfusion and iron chelation, have significantly improved the quality of life in patients over the years, but still fail to address the underlying cause of the diseases. A curative option, allogeneic bone marrow transplantation is available, but limited by the availability of suitable donors and graft-vs-host disease. Gene therapy offers an alternative approach to cure patients with hemoglobinopathies and aims at the direct recovery of the hemoglobin function via globin gene transfer. In the last 2 decades, gene transfer tools based on lentiviral vector development have been significantly improved and proven curative in several animal models for SCD and thalassemia. As a result, clinical trials are in progress and 1 patient has been successfully treated with this approach. However, there are still frontiers to explore that might improve this approach: the stoichiometry between the transgenic hemoglobin and endogenous hemoglobin with respect to the different globin genetic mutations; donor cell sourcing, such as the use of induced pluripotent stem cells (iPSCs); and the use of safer gene insertion methods to prevent oncogenesis. With this review we will provide insights about (1) the different lentiviral gene therapy approaches in mouse models and human cells; (2) current and planned clinical trials; (3) hurdles to overcome for clinical trials, such as myeloablation toxicity, insertional oncogenesis, and high vector expression; and (4) future perspectives for gene therapy, including safe harbors and iPSCs technology.
authors: Weill Cornell Medical College, Department of Pediatrics, Division of Hematology-Oncology, New York, NY 10021, USA.
authors: Alisa
authors: A
authors: Dong
authors: Stefano
authors: S
authors: Rivella
authors: Laura
authors: L
authors: Breda
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005319:Fetal Hemoglobin / Q000378:metabolism; D015316:Genetic Therapy; D006453:Hemoglobinopathies / Q000235:genetics* / Q000628:therapy*; D006801:Humans; D010641:Phenotype
chemical_list: D005319:Fetal Hemoglobin