Abstract
β-thalassemias and sickle cell anemia (SCA) are the most common monogenic diseases worldwide for which curative treatments remain a desired goal. Allogeneic hematopoietic stem cell transplantation (allo-HCT), - the only curative treatment currently available for hemoglobinopaties-, has a narrow application window whereas it incurs several immunological risks. 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 drug- independent without the immunological complications that normally accompany allo-HCT. Prior to the application of GT for hemoglobinopathies 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 (SCD) have been conducted or are in progress and 3 cases of transfusion independence in thalassemic β0/βΕ patients have been reported. In the present review, the prerequisites for successful implementation of GT, the tough pathway of GT for hemoglobinopathies towards the clinic and the knowledge gained from the first clinical trials as well as the remaining questions and challenges, will be discussed. Overall, after decades of research including achievements but pitfalls as well, the path to GT of human patients with hemoglobinopathies is currently open and highly promising...
Highlights
Stable and homogeneous expressionViral vector expression may be highly differential, since the result- group of M
T clinical trials for β-thalassemia and sickle cell disease (SCD) have rc been conducted or are in progress and 3 cases of transfusion indee pendence in thalassemic β0/βΕ patients have been reported
In view of a gene therapy clinical trial for thalassemia and in order to address safety and efficacy issues governing stem cell mobilization, we have previously investigated in two clinical trials, various CD34+ cell mobilization strategies using G-CSF-alone, Hydroxyurea (HU)+GCSF, Plerixafor-alone and Plerixafor+G-CSF
Summary
Viral vector expression may be highly differential, since the result- group of M. Due to the limitations of G-CSF mobilization in splenectomized patients with thalassemia and in other patients where gene therapy could serve as an alternative therapeutic option (sickle cell disease, Fanconi anemia),[57,61] we investigated, in a second trial (THAL002), Plerixafor (Mozobil) as a single mobilizing agent and in combination with G-CSF, when failure to collect sufficient HSC numbers by singlevide adequate ablation to allow transduced HSCs reach clinically relevant levels, while maintaining an adequate level of safety commensuagent mobilization (≥6x106/kg) was encountered.[62] The THAL002 trial rate with a Phase I clinical trial.[48] it would be important in this case, to counterbalance the low engraftment that would be expectenrolled 20 patients and showed that Plerixafor can rapidly and effectively mobilize CD34+ cells, without causing hyperleukocytosis in ed under these conditions, by using methods that ensure high levels of splenectomized patients. Efforts are made to minimize the risk of insertional oncogenesis and increase the efficacy of lentiviral globin vectors by genome-wide identification and functional characterization of human, novel, powerful and small-sized enhancer-blocking insulators to be incorporated in globin vectors and erythroid-specific enhancers to substitute for the conventional β-globin microLCR
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