文献类型：期刊文献

英文题名：Exploring the Potential Feasibility of Intra-articular Adeno-Associated Virus-Mediated Gene Therapy for Hemophilia Arthropathy

作者：Zhang, Feixu[1,2];Yan, Xiaobo[3];Li, Min[2];Hua, Baolai[3];Xiao, Xiao[2];Monahan, Paul E.[4,5,6];Sun, Junjiang[4,7]

机构：[1]East China Univ Sci & Technol, Sch Bioengn, Shanghai, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai, Peoples R China;[3]Yangzhou Univ, Clin Med Coll, Dept Hematol, Shuaifuyuan 1, Yangzhou 225001, Jiangsu, Peoples R China;[4]Univ N Carolina, Gene Therapy Ctr, 5027 Thurston Bldg, Chapel Hill, NC 27599 USA;[5]Univ N Carolina, Harold R Roberts Comprehens Hemophilia Diag & Tre, Chapel Hill, NC 27599 USA;[6]Spark Therapeut, Philadelphia, PA USA;[7]Univ N Carolina, Eshelman Sch Pharm, Div Mol Pharmaceut, Chapel Hill, NC 27599 USA

年份：2020

卷号：31

期号：7-8

起止页码：448

外文期刊名：HUMAN GENE THERAPY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000525024700001)】；

基金：The work was supported, in part, by a grant from the Novo Nordisk Hemophilia Research Fund China, an unrestricted grant from Novo Nordisk, Fundamental Research Funds for the Central Universities, and a grant from the National Natural Science Foundation of China (#81970171). Junjiang Sun received a research grant from Asklepios BioPharmaceutical during the preparation of the article.

语种：英文

外文关键词：hemophilia; arthropathy; intraarticular; recombinant human factor VIII; adeno-associated virus; neutralizing antibody

摘要：Hemophilia arthropathy (HA) represents the majority of morbidity in severe hemophilia patients, especially in resource-limited countries. Adeno-associated virus (AAV)-mediated gene therapy is showing promise for managing hemophilia. However, patients with neutralizing antibodies (NAbs) against AAV, and inhibitors to clotting factors, are excluded from such therapy. This study explored the feasibility of AAV-mediated local gene therapy for HA. Factor VIII knockout (FVIII-/-) mice, with or without a FVIII inhibitor, were subjected to hemarthrosis induction and treated with either intravenous (IV) or intraarticular (IA) recombinant human factor VIII (rhFVIII). To investigate whether rhFVIII carried the risk to develop a FVIII inhibitor, FVIII-/- mice were treated with three doses of IV or IA rhFVIII and inhibitor development was measured. In patients with established HA requiring synovial fluid aspiration, plasma, and synovial fluid were collected and measured for anti-AAV capsid IgG (serotypes 1-9 and 843) and NAbs for AAV843. IA rhFVIII provided better protection from synovitis compared with IV rhFVIII, with or without the FVIII inhibitor. While IV rhFVIII led to all FVIII-/- mice developing an FVIII inhibitor (n = 31, median 4.9 Bethesda units [BU]/mL), only 50% of the mice developed a FVIII inhibitor by IA administration, and at a lower titer (median 0.55 BU/mL). In hemophilia patients, total anti-AAV IgG was lowest for AAV4 and AAV5, both in plasma and synovial fluid. Anti-AAV IgGs in synovial fluid for most samples were lower or similar to the plasma levels. These results show that direct IA rhFVIII administration yields better protection against bleeding-induced joint damage, even in the presence of an inhibitor antibody. IA rhFVIII delivery carried a lower risk of FVIII inhibitor formation compared with IV FVIII. The anti-AAV antibody level in synovial fluid was similar or lower than the plasma level, supporting the feasibility of local gene therapy for managing HA.