Evaluation of early prophylactic corticosteroid administration on early safety and efficacy outcomes of adeno-associated virus gene therapy in the hemophilia dog model.
BACKGROUND: Prior to commercial withdrawal, adeno-associated virus (AAV) gene therapy was approved for the treatment of adults with severe hemophilia A. Mechanisms underlying variability, durability, and liver transaminitis are largely uncharacterized. OBJECTIVES: To evaluate the effects of prophylactic corticosteroid administration on AAV gene therapy outcomes in dogs with severe hemophilia A. METHODS: Seven dogs with hemophilia A received 6e13 vector genomes/kg of AAV5-canine factor (F)VIII. Four dogs received oral prednisolone (1 mg/kg/day) starting 3 hours preinfusion with dose-tapering over 6 weeks; three control dogs received no corticosteroids. Percutaneous liver biopsies were performed on detection of alanine aminotransferase (ALT) >2-fold the upper limit of normal. RESULTS: All dogs expressed therapeutic FVIII:C (8.7-56.1%), improved whole blood clot time, and decreased bleeding rates (pre = 6.11 vs post = 1.42 bleeds/year, P = .016) over 2 years post-AAV5-canine FVIII. Corticosteroid-treated dogs demonstrated a modest increase in mean FVIII:C at 2 years by chromogenic substrate assay (39.1%) compared with controls (29.5%), driven by one female with markedly elevated FVIII:C from day 54 onward. When analyzed by sex, all female dogs exhibited increased mean FVIII:C chromogenic substrate assay at 2 years (49.3%) compared with males (9.1%), regardless of prophylactic corticosteroid use. Prophylactic corticosteroids did not impact transient posttreatment elevations of proinflammatory cytokines, anti-AAV antibody formation, or ALT levels. One corticosteroid-treated dog experienced ALT > 4.3-fold the upper limit of normal at 18 weeks without impacting long-term FVIII:C expression. A liver biopsy showed diffuse, minimal periportal lymphocyte and neutrophil infiltration, consistent with nonspecific minimal hepatitis. CONCLUSIONS: Prophylactic corticosteroids were not clearly associated with increased transgene expression in dogs with hemophilia A.