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...

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Bibliographic Details
Published in:Molecular therapy 2021-04, Vol.29 (4), p.1625-1638
Main Authors: Breda, Laura, Ghiaccio, Valentina, Tanaka, Naoto, Jarocha, Danuta, Ikawa, Yasuhiro, Abdulmalik, Osheiza, Dong, Alisa, Casu, Carla, Raabe, Tobias D., Shan, Xiaochuan, Danet-Desnoyers, Gwenn A., Doto, Aoife M., Everett, John, Bushman, Frederic D., Radaelli, Enrico, Assenmacher, Charles A., Tarrant, James C., Hoepp, Natalie, Kurita, Ryo, Nakamura, Yukio, Guzikowski, Virginia, Smith-Whitley, Kim, Kwiatkowski, Janet L., Rivella, Stefano
Format: Article
Language:English
Subjects:
Anemia, Sickle Cell - blood
Anemia, Sickle Cell - genetics
Anemia, Sickle Cell - pathology
Anemia, Sickle Cell - therapy
Animals
beta-globinopathies
beta-Globins - genetics
beta-Globins - therapeutic use
beta-Thalassemia - blood
beta-Thalassemia - genetics
beta-Thalassemia - pathology
beta-Thalassemia - therapy
Bone Marrow Transplantation
gene addition
Gene Expression - genetics
gene therapy
Genetic Therapy
Genetic Vectors - genetics
Genetic Vectors - pharmacology
hematopoietic stem cells
Hemoglobins - genetics
Heterografts
Humans
lentiviral vectors
Lentivirus - genetics
Locus Control Region - genetics
Mice
Original
Transduction, Genetic
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Summary: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. [Display omitted] Increase of beta-globin expression by gene addition is critical to successfully curing patients with beta-thalassemia and sickle cell disease. Here, Breda and colleagues report genomic features that maximize transgene expression at low genome integration rates, preserving efficacy and safety and potentially reducing the burden of autologous bone marrow transplantation.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2020.12.036