Enhanced Transduction of Human Hematopoietic Stem Cells by AAV6 Vectors: Implications in Gene Therapy and Genome Editing.,Molecular Therapy - Nucleic Acids

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Enhanced Transduction of Human Hematopoietic Stem Cells by AAV6 Vectors: Implications in Gene Therapy and Genome Editing.
Molecular Therapy - Nucleic Acids ( IF 8.8 ) Pub Date : 2020-03-29 , DOI: 10.1016/j.omtn.2020.03.009
Hua Yang ₁ , Keyun Qing ₂ , Geoffrey D Keeler ₂ , Ling Yin ₃ , Mario Mietzsch ₄ , Chen Ling ₅ , Brad E Hoffman ₆ , Mavis Agbandje-McKenna ₄ , Mengqun Tan ₇ , Wei Wang ₈ , Arun Srivastava ₉

Affiliation

Department of Radiology, Institute of Cell and Gene Therapy, The Third Xiangya Hospital, Central South University, Changsha, China; Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA.
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA.
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL, USA.
State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, China.
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Department of Neuroscience, University of Florida College of Medicine, Gainesville, FL, USA.
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, China.
Department of Radiology, Institute of Cell and Gene Therapy, The Third Xiangya Hospital, Central South University, Changsha, China.
Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA; Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.

We have reported that of the 10 most commonly used adeno-associated virus (AAV) serotype vectors, AAV6 is the most efficient in transducing primary human hematopoietic stem cells (HSCs) in vitro, as well as in vivo. More recently, polyvinyl alcohol (PVA), was reported to be a superior replacement for human serum albumin (HSA) for ex vivo expansion of HSCs. Since HSA has been shown to increase the transduction efficiency of AAV serotype vectors, we evaluated whether PVA could also enhance the transduction efficiency of AAV6 vectors in primary human HSCs. We report here that up to 12-fold enhancement in the transduction efficiency of AAV6 vectors can be achieved in primary human HSCs with PVA. We also demonstrate that the improvement in the transduction efficiency is due to PVA-mediated improved entry and intracellular trafficking of AAV6 vectors in human hematopoietic cells in vitro, as well as in murine hepatocytes in vivo. Taken together, our studies suggest that the use of PVA is an attractive strategy to further improve the efficacy of AAV6 vectors. This has important implications in the optimal use of these vectors in the potential gene therapy and genome editing for human hemoglobinopathies such as β-thalassemia and sickle cell disease.

中文翻译：

通过AAV6载体增强人类造血干细胞的转导：在基因治疗和基因组编辑中的意义。

我们已经报道了在10种最常用的腺相关病毒（AAV）血清型载体中，AAV6在体外和体内都最有效地转导原代人造血干细胞（HSC）。最近，据报道，聚乙烯醇（PVA）是离体人体血清白蛋白（HSA）的优良替代品扩大HSC。由于已显示HSA可以提高AAV血清型载体的转导效率，因此我们评估了PVA是否还可以增强AHS6载体在原代人HSC中的转导效率。我们在此报告，在具有PVA的主要人类HSC中，AAV6载体的转导效率可提高多达12倍。我们还证明，转导效率的提高是由于体外人造血细胞以及体内鼠肝细胞中PVA介导的AAV6载体进入和细胞内运输的改善。综上所述，我们的研究表明，使用PVA是进一步提高AAV6载体功效的一种有吸引力的策略。这对于在人类血红蛋白病（例如β地中海贫血和镰状细胞病）的潜在基因治疗和基因组编辑中最佳使用这些载体具有重要意义。

更新日期：2020-03-29

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