OC 22.4 - Sustained correction of hereditary antithrombin deficiency in mice by AAV8-mediated gene delivery

Sunday, June 23, 2024

15:30 – 15:45 ICT

Room: Ballroom B2

Presenting Author(s)

Yanyi Tao, PhD

Department of Hematology, West China Hospital, Sichuan University.
chengdu, Sichuan, China (People's Republic)

Co-Author(s)

Hui Lu, PhD

PhD Student
Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
wuhan, Hubei, China (People's Republic)
CG

Chenggang Gao

PhD
Department of Critical Care Medicine, West China Hospital of Sichuan University, Sichuan, China.
Chengdu, Sichuan, China (People's Republic)
TN

Ting Niu

PhD
Department of Hematology, West China Hospital, Sichuan University, Chengdu, Sichuan, China
Chengdu, Sichuan, China (People's Republic)
YH

Yu Hu

PhD
Institution of Hematology, Wuhan Union Hospital, Tongji medical college, Huazhong University of Science and Technology
wuhan, Hubei, China (People's Republic)
LT

Liang V Tang

PhD
Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
wuhan, Hubei, China (People's Republic)

Background: Hereditary antithrombin（AT）deficiency is caused by mutations in the SERPINC1 gene, which is clinically manifested as venous thrombosis and predisposes to relapse. Patients with the disease are traditionally treated with prophylactic or on-demand oral anticoagulants, however, long-term oral anticoagulants have side effects and not necessarily effective.

Aims: To evaluate the effects of adeno-associated virus (AAV) carrying antithrombin by serotype 8 (AAV8/AT) on hereditary AT deficiency mice by gene therapy strategies.

Methods: AAV8/AT carrying luciferase was injected into AT+/- KO mice through the tail vein, and the expression of the carrier in mice was visualized by in vivo bioimaging technology. The plasma AT expression of AT+/- KO mice after treatment were continuously detected, and the observation period lasted for about 11 months. To assess whether the thrombophilia of AT-deficient mice was improved.

Results: Compared with untreated AT+/- KO mice, the plasma AT expression of AT+/- KO mice injected with medium-dose AAV8/AT returned to normal level at the eighth week (activity: from 43.4±3.9 % to 89.5±5.3%, p < 0.0001; antigen: from 133.6±12.5 ng/mL to 347.8±19.6 ng/mL, p < 0.0001) and maintained at the therapeutic level for up to 40 weeks. The inferior vena cava thrombosis model suggested that, the weight of thrombus formed in AT+/- KO mice treated with medium-dose AAV8/AT was significantly lighter compared with untreated AT+/- KO mice (10.32±1.79 mg versus 17.02±4.52 mg, P < 0.001), and there was no significant difference compared with that in wild-type mice (10.88±1.61 mg). The AAV8/AT vector did not have any adverse immunogenic events in vivo.

Conclusion(s): AAV8-mediated gene delivery can continuously correct the blood hypercoagulation state and rescue thrombophilia in AT-deficient mice. This gene therapy is safe and effective, providing potential curative applications for hereditary thrombophilia.