Elucidating the Mechanism Behind the AAV-Derived Factor VIII Assay Discrepancy
Highlights From the 30th Congress of ISTH

Elucidating the Mechanism Behind the AAV-Derived Factor VIII Assay Discrepancy

Presented by: Anna Sternberg, PhD, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Sternberg, B. Samelson-Jones, L. George1

1The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

Key Data Points

2-Stage Clotting Assay

Two experiments suggesting that the FVIII assay discrepancy is independent of vWF. The 2-stage clotting assay results on the left show the increased activity of transgene-derived FVIII (AAV-FVIII) compared to wild type recombinant FVIII (rFVIII-WT) as well as a recombinant FVIII with decreased affinity for vWF (rFVIII-E1682K). The graph on the right shows the similarity in the 1-stage assay (OSA)/chromogenic assay (CSA) ratio after infusion of AAV8-hFVIII into mice deficient in both FVIII and vWF when the OSA is performed in the presence or absence of vWF.

Comparison of AAV-FVIIIa Activity

Comparison of AAV-FVIIIa activity to recombinant WT-FVIIIa and recombinant FVIII variants with enhanced A2 stability (rFVIIIa-E1984V and rFVIIIa-VV).  AAV-FVIIIa and rFVIIIa-WT have similar activity compared to the increased activity in the recombinant variants with increased A2 affinity. These results suggest that differences in dissociation of the FVIII A2 subunit are unlikely to account for OSA/CSA factor assay discrepancies.

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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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