Preclinical development of lentiviral vector gene therapy for Diamond-Blackfan anemia syndrome.

Autor:	Bhoopalan SV; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: senthil.bhoopalan@stjude.org., Mayuranathan T; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Liu N; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Mayberry K; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Yao Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Zhang J; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Métais JY; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Yan KK; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Throm RE; St. Jude Vector Laboratory, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Ellis SR; Department of Biochemistry and Molecular Genetics, University of Louisville, Louisville, KY 40292, USA., Ju Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Han L; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Suryaprakash S; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Palmer LE; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Zhou S; Experimental Cellular Therapeutics Lab, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Yu J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Cheng Y; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Yen JS; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Gottschalk S; Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Weiss MJ; Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: senthil.bhoopalan@stjude.org.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Dec 12. Date of Electronic Publication: 2024 Dec 12.
DOI:	10.1016/j.ymthe.2024.12.020
Abstrakt:	Diamond-Blackfan anemia syndrome (DBAS) is an inherited bone marrow failure disorder caused by haploinsufficiency of ribosomal protein genes, most commonly RPS19. Limited access to patient hematopoietic stem/progenitor cells (HSPCs) is a major roadblock to developing novel therapies for DBAS. We developed a novel self-inactivating third-generation RPS19-encoding lentiviral vector (LV), termed "SJEFS-S19", for DBAS gene therapy. To facilitate LV design, optimize transduction and assess potential therapeutic efficacy, we leveraged a human cellular model of DBAS based on heterozygous disruption of RPS19 in healthy donor CD34 + HSPCs. We show that SJEFS-S19 LV can rescue DBAS-associated defects in ribosomal RNA processing, erythropoiesis and competitive bone marrow repopulation. Transduction of RPS19 +/- CD34 + HSPCs with SJEFS-S19 LV followed by xenotransplantation into immunodeficient mice generated a polyclonal HSPC population with normal multi-lineage differentiation and a diverse integration site profile resembling that of clinically proven LVs. Overall, these preclinical studies demonstrate the safety and efficacy of SJEFS-S19, a novel LV for future DBAS gene therapy. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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