An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs.
An Observational Study from Long-Term AAV Re-administration in Two Hemophilia Dogs.
复制标题
DOI：
10.1016/j.omtm.2018.07.011
复制
发表时间：
2018-09-21
期刊：
影响因子：
--
通讯作者：
Li C
中科院分区：
文献类型：
--
作者：
Sun J;Shao W;Chen X;Merricks EP;Wimsey L;Abajas YL;Niemeyer GP;Lothrop CD;Monahan PE;Samulski RJ;Nichols TC;Li C
腺相关病毒（AAV）载体已成功应用于血友病临床试验。然而，这种方法仅限于没有AAV中和抗体（NAb）的患者。在本研究中，我们探索了在8年前最初用AAV 8.犬FVIII治疗的血友病A犬中再次施用AAV的可行性。在两只NAb阴性狗中再次施用携带人因子VIII（hFVIII）的AAV 8载体沿着蛋白酶体抑制剂硼替佐米后，我们在两只狗中观察到表型改善，其在一只狗中持续存在。在另一只狗中，表型改善在再给药后59天消失，并且在第17天检测到针对衣壳的特异性细胞毒性T淋巴细胞（CTL），但未检测到针对hFVIII的特异性细胞毒性T淋巴细胞。在第59天观察到hFVIII抑制剂并逐渐增加。机制研究表明，促炎性细胞因子增加，免疫调节细胞因子减少，以及再给药后TdR降低。这些结果表明，hFVIII抑制剂的产生可能通过免疫应答激活导致治疗失败。有趣的是，AAV NAb滴度降低一半需要约30-50天。总的来说，本研究表明，在长期随访后重新给药相同的AAV血清型是可行的，并且AAV NAb动力学研究将为预测重新给药的疗效提供重要信息。
Adeno-associated virus (AAV) vectors have been successfully applied in hemophilia clinical trials. However, this approach is limited to patients without AAV-neutralizing antibodies (NAbs). In this study, we explored the feasibility of AAV re-administration in hemophilia A dogs treated initially 8 years ago with AAV8.canine FVIII. After the re-administration in two NAb-negative dogs with AAV8 vectors carrying human factor VIII (hFVIII), along with the proteasome inhibitor bortezomib, we observed a phenotypic improvement in both dogs that persisted in one dog. Phenotypic improvement disappeared at 59 days after re-administration in the other dog, and specific cytotoxic T lymphocytes (CTLs) to the capsid were detected at day 17, but not to hFVIII. hFVIII inhibitors were observed at day 59 and gradually increased. Mechanistic studies demonstrated an increase in pro-inflammatory cytokines, a decrease in immunomodulatory cytokines, as well as lower Tregs after re-administration. These results suggest that hFVIII inhibitor development may contribute to the therapeutic failure via immune response activation. Interestingly, it takes about 30–50 days for AAV NAb titers to decrease by half. Collectively, this study suggests that re-administration of the same AAV serotype after long-term follow-up is feasible and that the study of AAV NAb kinetics will provide important information for predicating the efficacy of re-administration.
登录
查看更多内容
影响因子：
5.1
作者：
Chaanine, A. H.;Nonnenmacher, M.;Kohlbrenner, E.;Jin, D.;Kovacic, J. C.;Akar, F. G.;Najjar, R. J.;Weber, T.
通讯作者：
Weber, T.
硼替佐米抑制TGF-β1，IL-10和CXCR4的表达，从而导致皮肤T细胞淋巴瘤细胞的存活率降低和迁移。
DOI：
10.4049/jimmunol.1402610
发表时间：
2015-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chang TP;Poltoratsky V;Vancurova I
通讯作者：
Vancurova I
影响因子：
12.8
作者：
Miller CH;Rice AS;Boylan B;Payne AB;Kelly FM;Escobar MA;Gill J;Leissinger C;Soucie JM;Hemophilia Inhibitor Research Study Investigators
通讯作者：
Hemophilia Inhibitor Research Study Investigators
影响因子：
3.6
作者：
LoDuca PA;Hoffman BE;Herzog RW
通讯作者：
Herzog RW
影响因子：
5.1
作者：
Li, C.;Narkbunnam, N.;Monahan, P. E.
通讯作者：
Monahan, P. E.