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    Poster Networking

    Hemophilia and Rare Bleeding Disorders

    Poster Networking Session

    PB0183 - Efficient Gene Transduction in Pigs and Macaques with the Engineered AAV Vector AAV.GT5 for Hemophilia B Gene Therapy

    Sunday, June 25, 2023
    18:30 – 19:30 ET
    Room: Exhibition

      Presenting Author(s)

    • YK

      Yuji Kashiwakura, PhD (he/him/his)

      Assistant Professor
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

      • Co-Author(s)

    • KE

      Kazuhiro Endo

      Associate Professor
      Department of Surgery, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • AU

      Atsushi Ugajin

      Assistant Professor
      Department of Radiology, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • TK

      Tomohiro Kikuchi

      Assistant Professor
      Department of Radiology, Jichi Medical University School of Medicine
      Shimotuke, Tochigi, Japan

    • SH

      Shuji Hishikawa

      Associate Professor
      Department of Surgery, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • HN

      Hitoyasu Nakamura

      Assistant Professor
      Department of Radiology, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • YK

      Yuko Katakai

      Veterinarian
      The Corporation for Production and Research of Laboratory Primates
      Tsukuba, Ibaraki, Japan

    • NB

      Nemekhbayar Baatartsogt

      Postdoctoral Fellow
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • TH

      Takafumi Hiramoto

      Research Associate
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • MH

      Morisada Hayakawa

      Assistant Professor
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • NK

      Nobuhiko Kamoshita

      Assistant Professor
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • SY

      Shoji Yamazaki

      Pharmacist
      Clinical Research Center, Jichi Medical University Hospital
      Shimotsuke, Tochigi, Japan

    • AK

      Akihiro Kume

      Professor
      Clinical Research Center, Jichi Medical University Hospital
      Shimotsuke, Tochigi, Japan

    • HM

      Harushi Mori

      Professor
      Department of Radiology, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • NS

      Naohiro Sata

      Professor
      Department of Surgery, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • YS

      Yoichi Sakata

      Professor
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    • SM

      Shin-ichi Muramatsu

      Professor
      Devision of Neurological Gene Therapy, Center for Open Innovation, Jichi Medical University
      Shimotsuke, Tochigi, Japan

    • Tsukasa Ohmori, MD, PhD (he/him/his)

      Professor
      Department of Biochemistry, Jichi Medical University School of Medicine
      Shimotsuke, Tochigi, Japan

    Background: Gene therapy for hemophilia using adeno-associated virus (AAV) vectors allows long-term coagulation factor expression.

    Aims: We examined the potential of a novel engineered liver-tropic AAV3B-based vector AAV.GT5 for hemophilia B gene therapy.

    Methods: We compared the efficacy of gene therapy between AAV.GT5 and AAV-Spark100 .

    Results: In vitro transduction with AAV.GT5 in human hepatocytes was more than 100 times higher than with AAV-Spark100, while in vivo transduction efficacy into the liver and the increase in coagulation factor IX (FIX) antigen following intravenous injection of these vectors were similar in PXB mice (chimeric mice with a humanized liver) and macaques. The discrepancy was due to the low recovery and short half-life of AAV.GT5 in blood, depending on the positive charge of the heparin-binding site in the original AAV3B. The intra-hepatic vascular administration of AAV.GT5, but not AAV-Spark100, enhanced vector transduction into the liver and reduced vector distribution to the kidney in pigs. In macaques, the intra-hepatic artery injection of AAV.GT5 yielded a comparable increase in FIX antigen with a one-third dosage of peripheral venous administration. Two of four macaques who received AAV.GT5 intravenously did not develop neutralizing antibodies (NAbs) against AAV.GT5, while AAV-Spark100 induced serotype-specific NAbs in all four macaques. The NAb produced after the administration was relatively specific to the serotype and less responsive to the other serotype. As a result, the administration of AAV.GT5 successfully boosted FIX expression in one animal previously given AAV-Spark100.

    Conclusion(s): AAV.GT5 has different biodistribution and immunogenic characteristics compared with AAV-Spark100, and the intra-hepatic vascular administration may lessen the vector dose and avoid vector distribution to other organs.