Long-term Vector Genome Outcomes and Immunogenicity of AAV FVIII Gene Transfer in the Hemophilia A Dog Model
Highlights From the ISTH 2020 Virtual Congress

Long-term Vector Genome Outcomes and Immunogenicity of AAV FVIII Gene Transfer in the Hemophilia A Dog Model

Paul Batty1, Choong-Ryoul Sihn2, Justin Ishida2, Aomei Mo1, Bridget Yates2, Christine Brown1, Lorianne Harpell1, Abbey Pender1, Chris B. Russell2, Sofia Sardo Infirri1, Richard Torres2, Andrew Winterborn3, Sylvia Fong2, David Lillicrap1

1Department of Pathology and Molecular Medicine, Queen's University, Kingston, Ontario, Canada.

2BioMarin Pharmaceutical, Novato, CA, USA.

3Animal Care Services, Queen's University, Kingston, Ontario, Canada.

Key Data Points

No significant difference was seen in FVIII:C with time in the animals that responsed to treatment (n = 6).

The diagram summarizes FVIII activity in the 8 dogs infused with B-domain deleted canine-FVIII AAV (AAV-cFVIII). FVIII activity was measured in cryopreserved plasma samples using both one-stage (OSA) and chromogenic (CSA) assays, with pooled canine normal plasma as a standard. Persistent, stable liver-derived FVIII expression was seen > 10 years after a single AAV-BDD-cFVIII infusion in 6 of 8 animals. The table compares the results of OSA and CSA, demonstrating the higher values of the OSA as seen in human studies. At the 9-12 year assessments for the 6 dogs that responded, FVIII:C activity ranged from 1.7%-8.6% (CSA) and 4.4%-14.9% (OSA).

Representative graphs showing presence of neutralizing antibodies (NAb) for a dog infused with AAV2 (yellow), AAV6 (pink), and AAV8 (green). No baseline capsid neutralizing antibodies were detected in untreated control dogs (n = 11). Some cross-reactivity was observed for non-dosed capsids in treated animals, and no significant reactivity was observed for AAV5 at any time point tested. Although NAb titer declined over time, substantial NAb activity remained at the end of the study, potentially preventing redosing with the same AAV serotype.



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Supported by educational grants from Bayer, BioMarin, CSL Behring, Freeline Therapeutics Limited, Pfizer Inc., Spark Therapeutics, and uniQure, Inc.

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