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.

-thalassemias: paradigmatic diseases for scientific discoveries and development of innovative therapies

“…Gene therapy may offer an alternative approach to cure patients with severe b-thalassemia, 163 as autologous hematopoietic stem cells (HSC) are isolated, genetically modified and returned to the same patient. Over recent years, the techniques and tools to achieve transfer of a curative b-globin gene using lentiviral vectors have been significantly improved and have proved to be curative in several animal models for b-thalassemia.…”

“…Over recent years, the techniques and tools to achieve transfer of a curative b-globin gene using lentiviral vectors have been significantly improved and have proved to be curative in several animal models for b-thalassemia. 163,164 As a result, clinical trials are in progress and several patients seemed to have been successfully treated with this approach. These encouraging results are now invigorating the field of gene transfer and cellular therapies.…”

α-Globin as a molecular target in the treatment of β-thalassemia

“…7,8 Gene therapy has made noteworthy, albeit slow, progress and is being tested in clinical trials in a limited number of patients. [9][10][11] However, the reported risks associated with the procedure, including development of leukemia by activation of proto-oncogenes, means much further work will be required to develop this as a common treatment. 12 Pharmacological augmentation of fetal hemoglobin (HbF) production has been a long-standing therapeutic objective and is already in clinical use for patients with severe sickle cell disease.…”

Wild-type macrophages reverse disease in heme oxygenase 1-deficient mice

“…Recent developments in gene therapy, induced pluripotent stem cell, and other cell reprogramming technologies open multiple opportunities for the development of new effective treatments for HMOX1-deficient patients. [34][35][36][37][38] …”