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    Oral Communication

    Hemophilia and Rare Bleeding Disorders

    Hemophilia Gene Therapy Basic Science

    OC 30.2 - Stable Factor VIII Expression and Improvement in Bleeding Phenotype Following Early Childhood Treatment with Adeno-Associated Viral Gene Therapy in the Severe Hemophilia A Dog Model

    Monday, June 26, 2023
    11:00 – 11:15 ET
    Room: 517
    Session Available As: Live-Stream and On-Demand
    Background: Adeno-associated viral (AAV) gene therapy has received conditional approvals for the treatment of adults with severe hemophilia A in Europe. Treatment during childhood might prevent joint bleeding and improve quality of life. With liver expansion during early life, there are concerns that AAV treatment in children will result in loss of expression with age.

    Aims: To evaluate the safety and efficacy of infant and neonatal AAV5-cFVIII treatment in the severe hemophilia A dog model.

    Methods: Severe hemophilia dogs received a codon-optimized AAV5-B-domain deleted canine Factor VIII (FVIII) construct with a hybrid liver promoter. Liver volume was calculated using magnetic resonance imaging, pre-treatment and 3, 6 and 12-months post-infusion. Percutaneous liver biopsies were performed pre-treatment and 2-weeks, 6 and 12-months post-treatment.

    Results: Five hemophilia dogs received a single vector infusion (dose=2.0e14 vg/kg) in two cohorts, treated at either 2-weeks (n=2) or 2-months of age (n=3). Based on epigenomic data, 2-months in dogs equates to 9-months in humans. Increases in body weight and liver volume were seen in the first six months post-treatment. Although, minimal FVIII expression was seen in dogs treated at 2-weeks, improvement in whole blood clot time (WBCT) and ROTEM clotting time (CT) was seen. Significant FVIII expression was seen in all dogs treated at 2-months, which was maintained despite a 3.3-fold increase in liver volume in the 6 months post AAV-cFVIII. In these dogs, normalization of WBCT and improvement in ROTEM CT were seen. Reduction in bleeding post AAV-cFVIII was seen in all dogs, with a single traumatic bleed occurring 2 days post-treatment. Alanine transaminase levels showed minor age-related increases. No FVIII inhibitors were detected.

    Conclusion(s): FVIII expression and improvement in bleeding phenotype was seen in severe hemophilia dogs treated at 2-months age. FVIII expression is maintained despite significant liver expansion. Further studies on liver biopsy samples ongoing.

    Learning Objectives:

    • Upon completion, participants will be able to list laboratory tests used to evaluate outcomes of Adeno-Associated Viral gene therapy in the hemophilia dog model
    • Upon completion, participants will be able to describe changes seen in liver volume and weight during early life in the hemophilia dog model
    • Upon completion, participants will be able to describe the differences seen in Factor VIII expression following Adeno-Associated Viral gene therapy in this study in hemophilia dogs treated at either 2-weeks or 2-months of age