Sustained Correction of Hereditary Antithrombin Deficiency in Mice by AAV8-Mediated Gene Delivery

BACKGROUND: Mutations in antithrombin ( SERPINC1 ) lead to the hereditary antithrombin deficiency. Conventional therapies for hereditary antithrombin deficiency are prophylactic or on-demand oral anticoagulants, which have poor compliance and side effects. This study explored the therapeutic efficacy of adeno-associated virus serotype 8 (AAV8)–mediated human SERPINC1 gene (AAV8-hSERPINC1) in AT (antithrombin)-deficiency mice. METHODS: AAV8-hSERPINC1 carrying luciferase was injected into AT +/− mice via tail vein injection at low, medium, and high doses. The biodistribution and expression of the carrier were visualized by in vivo bioimaging technology. Plasma AT levels were serially monitored by ELISA, and an inferior vena cava model was established to evaluate thrombotic propensity. Safety was evaluated by monitoring hepatic, renal, and cardiac function parameters and employing flow cytometry. RESULTS: A dose-dependent increase in AT expression was observed in AT +/− mice after AAV8-hSERPINC1 injection. Compared with the untreated mice, medium-dose treatment restored plasma AT activity and antigen in AT +/− mice to normal levels by week 8, with maintenance within the normal reference range for 40 weeks. In the venous thrombosis model, the rate of thrombosis in mice treated with medium-dose AAV8-hSERPINC1, rivaroxaban, low-molecular-weight-heparin, and wild-type mice were 60%, 60%, 70% and 60%, respectively. After AAV injection, transient elevations in hepatic transaminases and cytokines were observed in mice during a short-term period. CONCLUSIONS: Our study demonstrates that AAV8-hSERPINC1 gene delivery resulted in durable AT expression, sustained blood hypercoagulation state correction, thereby rescuing thrombophilia in AT-deficient male mice. These data support the long-term efficacy and safety of AAV gene therapy for hereditary antithrombin deficiency.