Success of Immune Tolerance Induction after AAV Gene Therapy in High-Responding Inhibitor Hemophilia a Dogs May be F8 Genotype Dependent

• Published in: Blood 2024-11, Vol.144 (Supplement 1), p.3579-3579
• Main Authors: Suber, Yani B, Doshi, Bhavya S, French, Robert A, Merricks, Elizabeth, Nichols, Timothy, Samelson-Jones, Ben
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2024-199820

Background The development of neutralizing alloantibodies (inhibitors) remains the major side effect of factor VIII (FVIII) replacement therapy for hemophilia A (HA). Inhibitors significantly increase morbidity and mortality. Though the advent of non-factor therapies for HA has dramatically improved hemostatic prophylaxis for inhibitor patients, inhibitor eradication and immune tolerance induction (ITI) remain essential therapeutic goals. Recombinant adeno-associated viral (rAAV) gene therapy for HA has almost completely excluded patients with current or a history of inhibitors. We have previously published that rAAV gene therapy with canine (c) FVIII induced immune tolerance in 5 HA dogs with inhibitors (Finn et al 2010, Doshi et al 2024). HA dogs are an outbred, long-lived, naturally occurring, large animal model that both recapitulates the HA bleeding phenotype and consistently develops inhibitors in a species-specific manner. These 5 previously described dogs all had F8 intron 22 inversion (F8-INV22), which is the most common genotype in severe HA patients and dogs. Both their inhibitor titer at the time of rAAV administration and their peak titer prior to rAAV was ≤21 Bethesda Units (BU). The success rate of ITI in inhibitor patients with large gene deletions is 80 BU. Within 1 year, both exhibited inhibitor eradication and anti-cFVIII IgG2 normalization. This inhibitor eradication was consistent with stringent immune tolerance, as evidenced by the absence of inhibitor re