Adeno-Associated Virus Neutralizing Antibodies in Large Animals and Their Impact on Brain Intraparenchymal Gene Transfer

Dan Wang; Li Zhong; Mengxin Li; Jia Li; Karen Tran; Lingzhi Ren; Ran He; Jun Xie; Richard P. Moser; Cara Fraser; Tim Kuchel; Miguel Sena-Esteves; Terence R. Flotte; Neil Aronin; Guangping Gao

Molecular Therapy: Methods & Clinical Development (Dec 2018)

Adeno-Associated Virus Neutralizing Antibodies in Large Animals and Their Impact on Brain Intraparenchymal Gene Transfer

Dan Wang,
Li Zhong,
Mengxin Li,
Jia Li,
Karen Tran,
Lingzhi Ren,
Ran He,
Jun Xie,
Richard P. Moser,
Cara Fraser,
Tim Kuchel,
Miguel Sena-Esteves,
Terence R. Flotte,
Neil Aronin,
Guangping Gao

Affiliations

Dan Wang: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA
Li Zhong: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA
Mengxin Li: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jia Li: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA
Karen Tran: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA
Lingzhi Ren: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA
Ran He: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA
Jun Xie: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA
Richard P. Moser: Department of Neurosurgery; University of Massachusetts Medical School, Worcester, MA 01605, USA
Cara Fraser: Preclinical, Imaging, and Research Laboratories, South Australian Health and Medical Research Institute, Gilles Plains, SA 5086, Australia
Tim Kuchel: Preclinical, Imaging, and Research Laboratories, South Australian Health and Medical Research Institute, Gilles Plains, SA 5086, Australia
Miguel Sena-Esteves: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA
Terence R. Flotte: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA 01605, USA
Neil Aronin: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author: Guangping Gao, PhD, Horae Gene Therapy Center, 368 Plantation Street, AS6-2049, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Guangping Gao: Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA 01605, USA; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Medical School, Worcester, MA 01605, USA; Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA; Viral Vector Core, University of Massachusetts Medical School, Worcester, MA 01605, USA; Corresponding author: Neil Aronin, MD, Department of Medicine, 368 Plantation Street, AS4-2051, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Journal volume & issue: Vol. 11
pp. 65 – 72

Abstract

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Pre-existing neutralizing antibody (NAb) against adeno-associated virus (AAV) commonly found in primates is a major host barrier that can severely compromise in vivo gene transfer by AAV vectors. To achieve proof-of-concept success in clinical development of recombinant AAV (rAAV)-based in vivo gene therapy, it is crucial to consider the potential interference of NAb and to enroll serologically compatible study subjects. In this study, we report a large AAV NAb dataset comprising multiple large animal species and AAV serotypes and compare two NAb assays based on in vitro or in vivo transduction inhibition, respectively. Together with previously published AAV seroepidemiology studies, these data can serve as a reference for selecting suitable serotypes, study subjects of large animal species, and potentially human patients for rAAV treatment. In addition, we modeled the intrathalamus rAAV9 delivery in the presence of circulating anti-AAV9 NAb generated by either pre-immunization or passive transfer of NAb-positive large animal serum to mice. The data showed that circulating NAb may not be the sole determinant to inhibit brain transduction. Other aspects of pre-existing AAV immunity following natural infection or rAAV administration may be further studied to establish a more accurate inclusion criterion for clinical studies employing intraparenchymal rAAV9 injections. Keywords: adeno-associated virus, CNS gene transfer, gene therapy, large animals, neutralizing antibody

Published in Molecular Therapy: Methods & Clinical Development

ISSN: 2329-0501 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Biology (General): Genetics; Science: Biology (General): Cytology
Website: http://www.cell.com/molecular-therapy-family/methods/latest-content

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