Conference Briefing: Frequency, Location and Nature of AAV Vector Insertions After Long-term Follow-up of FVIII Transgene Delivery in a Hemophilia A Dog Model

Highlights From the ISTH 2020 Virtual Congress

Frequency, Location and Nature of AAV Vector Insertions After Long-term Follow-up of FVIII Transgene Delivery in a Hemophilia A Dog Model

Paul Batty¹, Sylvia Fong², Matteo Franco³, Irene Gil-Farina³, Aomei Mo¹, Lorianne Harpell¹, Christine Hough¹, David Hurlbut¹, Abbey Pender¹, Sofia Sardo Infirri¹, Andrew Winterborn⁴, Manfred Schmidt³ and David Lillicrap¹

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

²BioMarin Pharmaceutical, Novato, CA, USA.

³GeneWerk GmbH, Heidelberg, Germany.

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

Key Data Points

The table on the left shows dose, capsid serotype, FVIII levels, and number of integration sites (IS) for the 8 dogs included in the study. Ten years after infusion, FVIII levels in 2 of the 8 animals were < 1% and ranged from 2.9% to 8.6% in the other 6 animals. Integration sites were analyzed using 2 methods (target-enrichment sequencing, TES, and linear amplification-mediated PCR, LAM-PCR). The graph on the right shows the relative distribution of IS for each animal.

Genomic DNA from 2 hepatic sites for each animal was analyzed for vector-genome integration. Integration forms (vector-genome) accounted for 4.6% and episomal forms (vector-vector) accounted for 95.4% of the read counts. These results indicate that the expression vectors maintained predominantly an episomal form 10+ years after infusion.

This table shows the 10 most common integration sites (chromosome, size, gene, and location) based on the TES method. Based on both sequencing methods, the most common integration sites were found in proximity to the KCNIP2, CLIC2, ABCB1, and F8 genes.

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Highlights From the ISTH 2020 Virtual Congress

Frequency, Location and Nature of AAV Vector Insertions After Long-term Follow-up of FVIII Transgene Delivery in a Hemophilia A Dog Model

Key Data Points

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