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Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice with FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies.
Hum Gene Ther 2017; 28(8):654-666HG

Abstract

While therapeutic expression of coagulation factors from adeno-associated virus (AAV) vectors has been successfully achieved in patients with hemophilia, neutralizing antibodies to the vector and inhibitory antibodies to the transgene severely limit efficacy. Indeed, approximately 40% of mice transduced with human factor VIII using the AAV8 serotype developed inhibitory antibodies to factor VIII (FVIII inhibitor), as well as extremely high titers (≥1:500) of neutralizing antibodies to AAV8. To correct hemophilia in these mice, AAV9, a serotype with low in vitro cross-reactivity (≤1:5) to anti-AAV8, was used to deliver mouse-activated factor VII (mFVIIa). It was found that within 6 weeks of systemic administration of 2 × 1013 particles/kg of AAV9/mFVIIa, hemophiliac mice with FVIII inhibitors and neutralizing antibodies (NAb) to AAV8 achieved hemostasis comparable to that in wild-type mice, as measured by rotational thromboelastometry. A level of 737 ng/mL mFVIIa was achieved after AAV9/mFVIIa adminstration compared to around 150 ng/mL without vector treatment, and concomitantly prothrombin time was shortened. Tissues collected after intra-articular hemorrhage from FVIII-deficient mice and mice with FVIII inhibitors were scored 4.7 and 5.5, respectively, on a scale of 0-10, indicating significant pathological damage. However, transduction with AAV9/mFVIIa decreased pathology scores to 3.6 and eliminated hemosiderin iron deposition in the synovium in most mice. Collectively, these results suggest that application of alternative serotypes of AAV vector to deliver bypassing reagents has the potential to correct hemophilia and prevent hemoarthrosis, even in the presence of FVIII inhibitor and neutralizing antibodies to AAV.

Authors+Show Affiliations

1 Gene Therapy Center, University of North Carolina , Chapel Hill, North Carolina. 2 Division of Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina.3 Department of Hematology, Peking Union Medical College Hospital , Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 4 Department of Hematology, Northern Jiangsu People's Hospital , Yangzhou, Jiangsu, China .1 Gene Therapy Center, University of North Carolina , Chapel Hill, North Carolina.1 Gene Therapy Center, University of North Carolina , Chapel Hill, North Carolina. 5 Department of Pharmacology, University of North Carolina , Chapel Hill, North Carolina.1 Gene Therapy Center, University of North Carolina , Chapel Hill, North Carolina. 6 Department of Pediatrics, University of North Carolina , Chapel Hill, North Carolina.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

28478688

Citation

Sun, Junjiang, et al. "Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice With FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies." Human Gene Therapy, vol. 28, no. 8, 2017, pp. 654-666.
Sun J, Hua B, Chen X, et al. Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice with FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies. Hum Gene Ther. 2017;28(8):654-666.
Sun, J., Hua, B., Chen, X., Samulski, R. J., & Li, C. (2017). Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice with FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies. Human Gene Therapy, 28(8), pp. 654-666. doi:10.1089/hum.2017.016.
Sun J, et al. Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice With FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies. Hum Gene Ther. 2017;28(8):654-666. PubMed PMID: 28478688.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gene Delivery of Activated Factor VII Using Alternative Adeno-Associated Virus Serotype Improves Hemostasis in Hemophiliac Mice with FVIII Inhibitors and Adeno-Associated Virus Neutralizing Antibodies. AU - Sun,Junjiang, AU - Hua,Baolai, AU - Chen,Xiaojing, AU - Samulski,Richard J, AU - Li,Chengwen, Y1 - 2017/05/05/ PY - 2017/5/10/pubmed PY - 2018/5/12/medline PY - 2017/5/9/entrez KW - FVIII inhibitor KW - activated factor VII KW - adeno-associated virus vector KW - gene therapy KW - hemophilia KW - neutralizing antibody SP - 654 EP - 666 JF - Human gene therapy JO - Hum. Gene Ther. VL - 28 IS - 8 N2 - While therapeutic expression of coagulation factors from adeno-associated virus (AAV) vectors has been successfully achieved in patients with hemophilia, neutralizing antibodies to the vector and inhibitory antibodies to the transgene severely limit efficacy. Indeed, approximately 40% of mice transduced with human factor VIII using the AAV8 serotype developed inhibitory antibodies to factor VIII (FVIII inhibitor), as well as extremely high titers (≥1:500) of neutralizing antibodies to AAV8. To correct hemophilia in these mice, AAV9, a serotype with low in vitro cross-reactivity (≤1:5) to anti-AAV8, was used to deliver mouse-activated factor VII (mFVIIa). It was found that within 6 weeks of systemic administration of 2 × 1013 particles/kg of AAV9/mFVIIa, hemophiliac mice with FVIII inhibitors and neutralizing antibodies (NAb) to AAV8 achieved hemostasis comparable to that in wild-type mice, as measured by rotational thromboelastometry. A level of 737 ng/mL mFVIIa was achieved after AAV9/mFVIIa adminstration compared to around 150 ng/mL without vector treatment, and concomitantly prothrombin time was shortened. Tissues collected after intra-articular hemorrhage from FVIII-deficient mice and mice with FVIII inhibitors were scored 4.7 and 5.5, respectively, on a scale of 0-10, indicating significant pathological damage. However, transduction with AAV9/mFVIIa decreased pathology scores to 3.6 and eliminated hemosiderin iron deposition in the synovium in most mice. Collectively, these results suggest that application of alternative serotypes of AAV vector to deliver bypassing reagents has the potential to correct hemophilia and prevent hemoarthrosis, even in the presence of FVIII inhibitor and neutralizing antibodies to AAV. SN - 1557-7422 UR - https://www.unboundmedicine.com/medline/citation/28478688/Gene_Delivery_of_Activated_Factor_VII_Using_Alternative_Adeno_Associated_Virus_Serotype_Improves_Hemostasis_in_Hemophiliac_Mice_with_FVIII_Inhibitors_and_Adeno_Associated_Virus_Neutralizing_Antibodies_ L2 - https://www.liebertpub.com/doi/full/10.1089/hum.2017.016?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -