Abstract
Gene therapy for β-thalassemia and sickle-cell disease is based on transplantation of genetically corrected, autologous hematopoietic stem cells. Preclinical and clinical studies have shown the safety and efficacy of this therapeutic approach, currently based on lentiviral vectors to transfer a β-globin gene under the transcriptional control of regulatory elements of the β-globin locus. Nevertheless, a number of factors are still limiting its efficacy, such as limited stem-cell dose and quality, suboptimal gene transfer efficiency and gene expression levels, and toxicity of myeloablative regimens. In addition, the cost and complexity of the current vector and cell manufacturing clearly limits its application to patients living in less favored countries, where hemoglobinopathies may reach endemic proportions. Gene-editing technology may provide a therapeutic alternative overcoming some of these limitations, though proving its safety and efficacy will most likely require extensive clinical investigation.
Highlights
HEMOGLOBINOPATHIES ARE INHERITED blood disorders characterized by defective synthesis of hemoglobin (Hb) chains or by the synthesis of mutated globin variants, such as the bA-E6V causing sickle-cell diseases (SCD)
Clinical development of gene therapy started in 2007 with the transplantation of hematopoietic stem-cell (HSC) transduced by the BGI lentiviral vectors (LVs) expressing the bT87Q globin in a patient affected by transfusiondependent HbE/b-thalassemia.[12]
Started with a first patient treated in France, with transplantation of CD34+ Hematopoietic stem/progenitor cells (HSPCs) transduced with the BB305 vector expressing the bA-T87Q globin at a dose of 5 · 106 cells/kg and an average vector copy number (VCN) of 1 after full myeloablative conditioning
Summary
Gene therapy for b-thalassemia and sickle-cell disease is based on transplantation of genetically corrected, autologous hematopoietic stem cells. Preclinical and clinical studies have shown the safety and efficacy of this therapeutic approach, currently based on lentiviral vectors to transfer a b-globin gene under the transcriptional control of regulatory elements of the b-globin locus. A number of factors are still limiting its efficacy, such as limited stem-cell dose and quality, suboptimal gene transfer efficiency and gene expression levels, and toxicity of myeloablative regimens. The cost and complexity of the current vector and cell manufacturing clearly limits its application to patients living in less favored countries, where hemoglobinopathies may reach endemic proportions. Gene-editing technology may provide a therapeutic alternative overcoming some of these limitations, though proving its safety and efficacy will most likely require extensive clinical investigation
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