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Sustained Correction of Hereditary Antithrombin Deficiency in Mice by AAV8-Mediated Gene Delivery
Yanyi Tao1, Hui Lu1, Tingting Wu2,3,4
1Department of Hematology, West China Hospital, Sichuan University, Chengdu (Y.T.).
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.
Insights
Gene therapy using AAV8-hSERPINC1 effectively restored antithrombin (AT) levels and corrected hypercoagulation in AT-deficient mice. This approach shows promise for treating hereditary antithrombin deficiency with durable, long-term efficacy and safety.
Area of Science:
- Genetics
- Molecular Biology
- Gene Therapy
Background:
- Hereditary antithrombin deficiency results from SERPINC1 mutations.
- Current treatments for antithrombin deficiency involve oral anticoagulants with compliance issues and side effects.
- Gene therapy offers a potential alternative for managing antithrombin deficiency.
Purpose of the Study:
- To evaluate the therapeutic efficacy of adeno-associated virus serotype 8 (AAV8)-mediated human SERPINC1 gene delivery (AAV8-hSERPINC1) in antithrombin (AT)-deficient mice.
- To assess the durability and safety of AAV8-hSERPINC1 gene therapy for hereditary antithrombin deficiency.
Main Methods:
- AAV8-hSERPINC1 was administered to AT-deficient mice at varying doses.
- In vivo bioimaging tracked carrier biodistribution and expression.
- Plasma AT levels were monitored via ELISA, and thrombotic propensity was assessed using a venous thrombosis model.
- Safety was evaluated through biochemical markers and flow cytometry.
Main Results:
- AAV8-hSERPINC1 administration led to a dose-dependent increase in AT expression.
- Medium-dose treatment normalized plasma AT levels for up to 40 weeks.
- Gene therapy demonstrated comparable efficacy to anticoagulants in reducing thrombosis rates.
- Transient elevations in liver enzymes and cytokines were observed post-injection.
Conclusions:
- AAV8-hSERPINC1 gene delivery provides durable antithrombin expression and corrects hypercoagulation.
- Gene therapy effectively rescues thrombophilia in AT-deficient mice.
- These findings support the long-term efficacy and safety of AAV gene therapy for hereditary antithrombin deficiency.
