“Lentiviral vector ALS20 yields high hemoglobin levels with low genomic integrations for treatment of beta-globinopathies”
Lentiviral vector ALS20 yields high hemoglobin levels with low genomic integrations for treatment of beta-globinopathies
Ongoing clinical trials for treatment of beta-globinopathies by gene therapy involve the transfer of the beta-globin gene, which requires integration of three to four copies per genome in most target cells. This high proviral load may increase genome toxicity, potentially limiting the safety of this therapy and relegating its use to total body myeloablation. We hypothesized that introducing an additional hypersensitive site from the locus control region, the complete sequence of the second intron of the beta-globin gene, and the ankyrin insulator may enhance beta-globin expression. We identified a construct, ALS20, that synthesized significantly higher adult hemoglobin levels than those of other constructs currently used in clinical trials. These findings were confirmed in erythroblastic cell lines and in primary cells isolated from sickle cell disease patients. Bone marrow transplantation studies in beta-thalassemia mice revealed that ALS20 was curative at less than one copy per genome. Injection of human CD34+ cells transduced with ALS20 led to safe, long-term, and high polyclonal engraftment in xenograft experiments. Successful treatment of beta-globinopathies with ALS20 could potentially be achieved at less than two copies per genome, minimizing the risk of cytotoxic events and lowering the intensity of myeloablation.
Gene therapy holds potential for the treatment of patients affected by beta-globinopathies.However,initial clinical trials run by Bluebird Bio in beta-thalassemia patients reported relatively low integration of the BB305 vector(withavectorcopynumber[VCN]<2) and suboptimal hemoglobin (Hb) synthesis. Similarly, BB305 exhibited insufficient expression of vector-derived Hb for treatment of sickle cell disease(SCD), and it only ameliorated SCD in one out of seven children affected by the disease. Nonetheless, transduction efficiency was improved in the most recent phase III trials, reaching VCN3–4, and transfusion independence was reported in four out of five patients with non-beta 0 beta 0 genotypes and in three out of four patients with severe beta 0 beta 0 or IVS1-110 genotypes.
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