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Characterisation of Adeno-Associated Virus Vector Persistence After Long-Term Follow-up in the Haemophilia A Dog Model
Highlights From the 14th Annual Congress of EAHAD

Characterisation of Adeno-Associated Virus Vector Persistence After Long-Term Follow-up in the Haemophilia A Dog Model

P. Batty1, S. Fong2, M. Franco3, I. Gil‐Farina3, C.‐R. Sihn2, A. Mo1, L. Harpell1, C. Hough1, D. Hurlbut1, A. Pender1, A. Winterborn4, M. Schmidt3, D. Lillicrap1

1Department of Pathology and Molecular Medicine, Queen’s University, Kingston, Canada

2BioMarin Pharmaceutical, Novato, United States

3GeneWerk GmbH, Heidelberg, Germany

4Animal Care Services, Queen’s University, Kingston, Canada

Key Data Points

Intra-hepatic Differences in AAV-FVIII DNA Distribution

In this study, 8 dogs were treated with a B-domain deleted canine FVIII AAV construct. After a median of 10.8 years follow-up, stable average FVIII levels of 5.7% were seen in the responding (n=6) dogs. AAV-FVIII DNA was detected in the liver of all dogs regardless of their treatment response. The graph above shows the AAV-FVIII copy numbers from multiple liver samples/regions. Some dogs demonstrated similar AAV-FVIII copy numbers (eg ELI & FLO) regardless of the region studied, whereas in others (eg JUN), there was more marked variation.

Integration Events Occurred Mainly in Non-coding Regions of the Canine Genome
The table on the left shows dose, final FVIII levels, and number of integration sites (IS) for the 8 dogs included in the study (color coding in dose column represents AAV serotype, yellow = AAV2, pink = AAV6 and cyan = AAV8. * = non-responding dogs). The median integration frequency was 9.55e-4 IS/cell, with the majority (93.8%) of IS occurring in intergenic regions of the dog genome. The most common integration sites (CIS) were in proximity to KCNIP2, CLIC2, ABCB1, F8, chymostrypsinogen B1-like, and albumin. The graph on the right shows the relative distribution of IS for each animal. Despite integration events occurring in all animals, no hepatic tumors were found at post-mortem.

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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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