An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs

Junjiang Sun; Wenwei Shao; Xiaojing Chen; Elizabeth P. Merricks; Lauren Wimsey; Yasmina L. Abajas; Glenn P. Niemeyer; Clinton D. Lothrop; Paul E. Monahan; R. Jude Samulski; Timothy C. Nichols; Chengwen Li

Molecular Therapy: Methods & Clinical Development (Sep 2018)

An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs

Junjiang Sun,
Wenwei Shao,
Xiaojing Chen,
Elizabeth P. Merricks,
Lauren Wimsey,
Yasmina L. Abajas,
Glenn P. Niemeyer,
Clinton D. Lothrop,
Paul E. Monahan,
R. Jude Samulski,
Timothy C. Nichols,
Chengwen Li

Affiliations

Junjiang Sun: Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Wenwei Shao: Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Xiaojing Chen: Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Elizabeth P. Merricks: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Lauren Wimsey: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Yasmina L. Abajas: Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Glenn P. Niemeyer: Department of Biochemistry, University of Alabama at Birmingham, Birmingham, AL, USA
Clinton D. Lothrop: Department of Biochemistry, University of Alabama at Birmingham, Birmingham, AL, USA
Paul E. Monahan: Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
R. Jude Samulski: Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Timothy C. Nichols: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Chengwen Li: Gene Therapy Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Corresponding author: Chengwen Li, Gene Therapy Center, University of North Carolina at Chapel Hill, 104 Manning Dr., Chapel Hill, NC 27599, USA.

Journal volume & issue: Vol. 10
pp. 257 – 267

Abstract

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Adeno-associated virus (AAV) vectors have been successfully applied in hemophilia clinical trials. However, this approach is limited to patients without AAV-neutralizing antibodies (NAbs). In this study, we explored the feasibility of AAV re-administration in hemophilia A dogs treated initially 8 years ago with AAV8.canine FVIII. After the re-administration in two NAb-negative dogs with AAV8 vectors carrying human factor VIII (hFVIII), along with the proteasome inhibitor bortezomib, we observed a phenotypic improvement in both dogs that persisted in one dog. Phenotypic improvement disappeared at 59 days after re-administration in the other dog, and specific cytotoxic T lymphocytes (CTLs) to the capsid were detected at day 17, but not to hFVIII. hFVIII inhibitors were observed at day 59 and gradually increased. Mechanistic studies demonstrated an increase in pro-inflammatory cytokines, a decrease in immunomodulatory cytokines, as well as lower Tregs after re-administration. These results suggest that hFVIII inhibitor development may contribute to the therapeutic failure via immune response activation. Interestingly, it takes about 30–50 days for AAV NAb titers to decrease by half. Collectively, this study suggests that re-administration of the same AAV serotype after long-term follow-up is feasible and that the study of AAV NAb kinetics will provide important information for predicating the efficacy of re-administration. Keywords: AAV, hemophilia, neutralizing antibodies, NAbs, re-administration, human factor VIII, hFVIII, hFVIII inhibitor

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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