Gene therapy for thalassemia

Haema 2016; 7(1): 81-91

by Garyfalia Karponi,1 Evangelia Yannaki1,2

1Gene and Cell Therapy Center, Hematology-Bone Marrow Transplantation Unit, George Papanicolaou Hospital, Thessaloniki, Greece,
2Department of Medicine, University of Washington, Seattle, WA, USA

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β-thalassemia is the most common monogenetic disease worldwide. The standard of care consists in lifelong transfusions combined with iron chelation and has substantially improved the life expectancy of the patients. However, strict compliance to the treatment severely compromises the patients’ quality of life, while it constitutes a significant financial burden for national economies. Failing to comply with the conventional treatment, patients are exposed to life-threatening complications. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is the only curative treatment available but it has a narrow application to those patients having a suitable donor as well as young patients without organ damage. Gene therapy (GT), that is the autologous transplantation of genetically modified hematopoietic stem cells (CD34+), represents a promising new therapeutic strategy which is anticipated to reestablish effective hemoglobin production and render patients transfusion and chelation independent without the immunological complications that normally accompany allo-HCT. Prior to the application of GT for thalassemia in the clinic, many years of extensive preclinical research were spent for the optimization of the gene transfer tools and conditions. To date, three GT clinical trials for β-thalassemia and sickle cell disease have been conducted or are in progress and 3 cases of transfusion independence in thalassemic β0/βΕ patients have been reported. However, the design of clinical GT protocols for hemoglobinopathies still remains controversial among researchers in the field. In particular, the optimal intensity of the conditioning, the dose range of genetically modified CD34+ cells to be infused, the optimal autologous graft source, further improvements of β-globin vectors and foremost, the ambiguous need of surplus safety features in the vector and clinical protocol design are issues that still need to be addressed, thus pointing out thalassemia gene therapy as one of the most challenging approaches in the GT field of genetic disorders. In the present review, the prerequisites to successful implementation of GT for thalassemia, as well as the tough pathway of GT for hemoglobinopathies towards the clinic and the knowledge gained from the first clinical trials along with the remaining questions and challenges, will be discussed. Overall, after decades of research including achievements but pitfalls as well, the path to thalassemia GT in humans is currently open and highly promising.