Michel Sadelain, MD, PhD, Center for Cell Engineering, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
The goal of globin gene therapy is to restore the capacity of autologous hematopoietic stem cells (HSCs) to generate red blood cells (RBCs) with normal hemoglobin content in thalassemic subjects and prevent sickling of RBCs in subjects with sickle cell disease. To this end, a sufficient number of the patient’s own HSCs need to be transduced with an erythroid-specific vector encoding a globin gene and engrafted following adequate host conditioning. We demonstrated over a decade ago that lentiviral vectors encoding the human ß-globin gene and an optimized combination of transcription control elements are efficiently transduced and expressed in mouse models of globin disorders. Having improved vector production to attain clinically relevant vector titers and demonstrated the safety and efficacy of GCSF mobilization of CD34+ cells in thalassemic adults, we have now initiated a clinical study to evaluate this approach in patients with ß-thalassemia major (NCT01639690). The application of this approach to sickle cell disease poses additional challenges. While a lower level of globin transgene expression may be sufficient to prevent hemoglobin S polymerization than the level required to correct severe thalassemia, the collection of HSCs, their transduction and their engraftment require further optimization. Emerging technologies for targeted globin gene delivery and gene repair will also be discussed