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Superior human hepatocyte transduction with adeno-associated virus vector serotype 7

Gene Therapy volume 26, pages 504–514 (2019)Cite this article

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Abstract

Although therapeutic outcomes have been achieved in hemophilia patients after delivery of clotting factor genes to the liver using adeno-associated virus (AAV) vectors, it is well known that the preclinical results generated from hemophilia animal models have not been directly predictive of successful translation in humans. To address this discrepancy humanized mouse models have recently been used to predict AAV transduction efficiency for human hepatocytes. In this study we evaluated AAV vector transduction from several serotypes in human liver hepatocytes xenografted into chimeric mice. After systemic administration of AAV vectors encoding a GFP transgene in humanized mice, the liver was harvested for either immunohistochemistry staining or flow cytometry assay for AAV human hepatocyte transduction analysis. We observed that AAV7 consistently transduced human hepatocytes more efficiently than other serotypes in both immunohistochemistry assay and flow cytometry analysis. To better assess the future application of AAV7 for systemic administration in the treatment of hemophilia or other liver diseases, we analyzed the prevalence of neutralizing antibodies (NAbs) to AAV7 in sera from healthy subjects and patients with hemophilia. In the general population, the prevalence of NAbs to AAV7 was lower than that of AAV2 or AAV3B. However, a higher prevalence of AAV7 NAbs was found in patients with hemophilia. In summary, results from this study suggest that AAV7 vectors should be considered as an effective vehicle for human liver targeting in future clinical trials.

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Acknowledgements

We thank UNC Vector Core for AAV vector production. The authors acknowledge the UNC Histological Research Core and Flow Cytometry Core Facilities for their assistance in liver immunohistochemistry and flow cytometry analysis. This work was supported by National Institutes of Health Grants R01HL125749 and R01HL144661 (to TCN and CL), and R01AI117408 and P01HL112761 (to RJS and CL).

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Authors and Affiliations

  1. Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Wenwei Shao, Xiaolei Pei, Charles Askew, Amanda Dobbins, Xiaojing Chen, R. Jude Samulski & Chengwen Li

  2. Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China

    Xiaolei Pei

  3. Department of Surgery, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Caibin Cui & David A. Gerber

  4. Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Yasmina L. Abajas & Chengwen Li

  5. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    R. Jude Samulski

  6. Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Timothy C. Nichols

  7. Carolina Institute for Developmental Disabilities, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA

    Chengwen Li

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  1. Wenwei Shao
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Correspondence to Chengwen Li.

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Conflict of interest

RJS is the founder and a shareholder at Asklepios BioPharmaceutical and Bamboo Therapeutics, Inc. He holds patents that have been licensed by UNC to Asklepios Biopharmaceutical, for which he receives royalties. He has consulted for Baxter Healthcare and has received payment for speaking. CL is a cofounder of Bedrock Therapeutics, Inc. He has licensed patents by UNC and has received royalties from Bedrock Therapeutics and Asklepios Biopharmaceutical. The other authors declare that they have no conflict of interest.

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Shao, W., Pei, X., Cui, C. et al. Superior human hepatocyte transduction with adeno-associated virus vector serotype 7. Gene Ther 26, 504–514 (2019). https://doi.org/10.1038/s41434-019-0104-5

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