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. Sabatino^2,5

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

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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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

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