An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs
Autor: | Lauren E. Wimsey, Glenn P. Niemeyer, Chengwen Li, Clinton D. Lothrop, Xiaojing Chen, Timothy C. Nichols, R. Jude Samulski, Junjiang Sun, Yasmina L. Abajas, Wenwei Shao, Paul E. Monahan, Elizabeth P. Merricks |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Serotype lcsh:QH426-470 re-administration hFVIII inhibitor viruses Article Virus 03 medical and health sciences Immune system hemophilia Genetics medicine Cytotoxic T cell neutralizing antibodies lcsh:QH573-671 Molecular Biology biology human factor VIII lcsh:Cytology business.industry Bortezomib AAV hFVIII 3. Good health lcsh:Genetics Titer 030104 developmental biology Immunology Proteasome inhibitor biology.protein Molecular Medicine NAbs Antibody business medicine.drug |
Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 10, Iss, Pp 257-267 (2018) Molecular Therapy. Methods & Clinical Development |
ISSN: | 2329-0501 |
Popis: | 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 |
Databáze: | OpenAIRE |
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