Abstract
Gene therapy clinical trials require rigorous non-clinical studies in the most relevant models to assess the benefit-to-risk ratio. To support the clinical development of gene therapy for β-thalassemia, we performed in vitro and in vivo studies for prediction of safety. First we developed newly GLOBE-derived vectors that were tested for their transcriptional activity and potential interference with the expression of surrounding genes. Because these vectors did not show significant advantages, GLOBE lentiviral vector (LV) was elected for further safety characterization. To support the use of hematopoietic stem cells (HSCs) transduced by GLOBE LV for the treatment of β-thalassemia, we conducted toxicology, tumorigenicity, and biodistribution studies in compliance with the OECD Principles of Good Laboratory Practice. We demonstrated a lack of toxicity and tumorigenic potential associated with GLOBE LV-transduced cells. Vector integration site (IS) studies demonstrated that both murine and human transduced HSCs retain self-renewal capacity and generate new blood cell progeny in the absence of clonal dominance. Moreover, IS analysis showed an absence of enrichment in cancer-related genes, and the genes targeted by GLOBE LV in human HSCs are well known sites of integration, as seen in other lentiviral gene therapy trials, and have not been associated with clonal expansion. Taken together, these integrated studies provide safety data supporting the clinical application of GLOBE-mediated gene therapy for β-thalassemia.
Highlights
IntroductionThe development of retroviral vectors and optimized transduction protocols has permitted gene transfer into hematopoietic stem and progenitor cells (HSPCs), leading to the application and translation of gene therapy strategies for a number of hematopoietic diseases and leukodystrophies (reviewed in Dunbar et al.,[1] Eichler et al.,[2] Aiuti et al.,[3] Biffi et al.,[4] and Ribeil et al.[5]).b-Thalassemia, an inherited anemia characterized by reduced or absent production of hemoglobin b chains, was one of the first candidate diseases for gene therapy.[6]
The development of retroviral vectors and optimized transduction protocols has permitted gene transfer into hematopoietic stem and progenitor cells (HSPCs), leading to the application and translation of gene therapy strategies for a number of hematopoietic diseases and leukodystrophies.b-Thalassemia, an inherited anemia characterized by reduced or absent production of hemoglobin b chains, was one of the first candidate diseases for gene therapy.[6]
These data indicate that the proportion of genetically modified nucleated progenitor cells necessary to achieve a therapeutic level of circulating red blood cells (RBCs) is within the frequency of gene transfer by b-globin lentiviral vector (LV).[10]
Summary
The development of retroviral vectors and optimized transduction protocols has permitted gene transfer into hematopoietic stem and progenitor cells (HSPCs), leading to the application and translation of gene therapy strategies for a number of hematopoietic diseases and leukodystrophies (reviewed in Dunbar et al.,[1] Eichler et al.,[2] Aiuti et al.,[3] Biffi et al.,[4] and Ribeil et al.[5]).b-Thalassemia, an inherited anemia characterized by reduced or absent production of hemoglobin b chains, was one of the first candidate diseases for gene therapy.[6]. The development of retroviral vectors and optimized transduction protocols has permitted gene transfer into hematopoietic stem and progenitor cells (HSPCs), leading to the application and translation of gene therapy strategies for a number of hematopoietic diseases and leukodystrophies (reviewed in Dunbar et al.,[1] Eichler et al.,[2] Aiuti et al.,[3] Biffi et al.,[4] and Ribeil et al.[5]). Allogeneic hematopoietic stem cell transplantation (HSCT) is a cure only available for less than 30% of patients.[7] The benefits and limitations of current therapies for b-thalassemia are well discussed by Cappellini et al.[8] Ex vivo engineering of autologous HSPCs and administration of genetically modified cells potentially represents a cure applicable to all patients regardless of donor availability and free from transplant-related immunological complications such as graft rejection and graft versus host disease. Non-clinical studies conducted in human HSPCs in vitro and murine models in vivo, as well as the first clinical trial, have demonstrated the feasibility of the gene therapy approach for the treatment of b-thalassemia.[11,12]
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