Novel lentiviral vectors for gene therapy of sickle cell disease combining gene addition and gene silencing strategies.

Autor:	Brusson M; Université de Paris, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR1163, 75015 Paris, France., Chalumeau A; Université de Paris, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR1163, 75015 Paris, France., Martinucci P; Université de Paris, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR1163, 75015 Paris, France., Romano O; Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.; Department of Molecular Medicine, University of Padova, 35131 Padova, Italy., Felix T; Université de Paris, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR1163, 75015 Paris, France., Poletti V; Woman and Child Health Department, University of Padova, Padova, Italy.; Harvard Medical School, Dana Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, USA.; Pediatric Research Institute, City of Hope, Padova, Italy., Scaramuzza S; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy., Ramadier S; Université de Paris, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR1163, 75015 Paris, France., Masson C; Paris-Descartes Bioinformatics Platform, Imagine Institute, 75015 Paris, France., Ferrari G; San Raffaele Telethon Institute for Gene Therapy (SR-TIGET), IRCCS San Raffaele Scientific Institute, Milan, Italy.; Vita-Salute, San Raffaele University, Milan, Italy., Mavilio F; Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.; Department of Molecular Medicine, University of Padova, 35131 Padova, Italy., Cavazzana M; Université de Paris, 75015 Paris, France.; Imagine Institute, 75015 Paris, France.; Biotherapy Department and Clinical Investigation Center, Assistance Publique Hôpitaux de Paris, INSERM, 75015 Paris, France., Amendola M; Genethon, 91000 Evry, France.; Université Paris-Saclay, University Evry, INSERM, Genethon, Integrare Research Unit UMR_S951, 91000 Evry, France., Miccio A; Université de Paris, Imagine Institute, Laboratory of Chromatin and Gene Regulation During Development, INSERM UMR1163, 75015 Paris, France.
Jazyk:	angličtina
Zdroj:	Molecular therapy. Nucleic acids [Mol Ther Nucleic Acids] 2023 Mar 22; Vol. 32, pp. 229-246. Date of Electronic Publication: 2023 Mar 22 (Print Publication: 2023).
DOI:	10.1016/j.omtn.2023.03.012
Abstrakt:	Sickle cell disease (SCD) is due to a mutation in the β-globin gene causing production of the toxic sickle hemoglobin (HbS; α 2 β S 2 ). Transplantation of autologous hematopoietic stem and progenitor cells (HSPCs) transduced with lentiviral vectors (LVs) expressing an anti-sickling β-globin (βAS) is a promising treatment; however, it is only partially effective, and patients still present elevated HbS levels. Here, we developed a bifunctional LV expressing βAS3-globin and an artificial microRNA (amiRNA) specifically downregulating β S -globin expression with the aim of reducing HbS levels and favoring βAS3 incorporation into Hb tetramers. Efficient transduction of SCD HSPCs by the bifunctional LV led to a substantial decrease of β S -globin transcripts in HSPC-derived erythroid cells, a significant reduction of HbS + red cells, and effective correction of the sickling phenotype, outperforming βAS gene addition and BCL11A gene silencing strategies. The bifunctional LV showed a standard integration profile, and neither HSPC viability, engraftment, and multilineage differentiation nor the erythroid transcriptome and miRNAome were affected by the treatment, confirming the safety of this therapeutic strategy. In conclusion, the combination of gene addition and gene silencing strategies can improve the efficacy of current LV-based therapeutic approaches without increasing the mutagenic vector load, thus representing a novel treatment for SCD. Competing Interests: M.B., F.M., M.C., M.A., and A.M. are the inventors of two patents describing bifunctional LVs for hemoglobinopathies. (© 2023 The Authors.)
Databáze:	MEDLINE
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