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AAV Integration Analysis After Long Term Follow-up in Hemophilia A Dogs Reveals the Genetic Consequences of AAV-Mediated Gene Correction
Highlights from the ASGCT 23rd Annual Meeting

AAV Integration Analysis After Long Term Follow-up in Hemophilia A Dogs Reveals the Genetic Consequences of AAV-Mediated Gene Correction

John K. Everett1, Giang N. Nguyen2, Hayley Raymond1, Aiofe Roche1, Samita Kafle2, Christian Wood2, Jacob Leiby1, Elizabeth P. Merricks3, Haig H. Kazazian4, Timothy C. Nichols3, Frederic D. Bushman1, Denise E. Sabatino2,5

1Department of Microbiology, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA

2The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA

3Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC

4Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD

5Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA

Key Data Points

This study involved long-term (up to 10 years) follow-up of 9 hemophilia A dogs treated with canine FVIII (cFVIII) gene therapy. The cFVIII gene was delivered to HA dogs using AAV8 or AAV9 using two delivery approaches: two chain delivery that co-delivered the heavy chain and the light chain in 2 separate vectors, or B-domain deleted cFVIII in a single AAV8 vector.

Vector copy number and integration target site analyses demonstrated expanded clones with integrated AAV molecules, including a clone containing an intact vector. No dogs demonstrated evidence of tumorigenesis, suggesting the clonal expansion and integration events were not associated with malignancies.

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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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