Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children.
Development of an AAV DNA-based synthetic vector for the potential gene therapy of hemophilia in children.
复制标题
DOI：
10.3389/fmicb.2022.1033615
复制
发表时间：
2022
影响因子：
5.2
通讯作者：
Srivastava, Arun
中科院分区：
文献类型：
--
作者：
Shoti, Jakob;Qing, Keyun;Srivastava, Arun
重组AAV血清型载体及其变异体已经或正在用于血友病的基因治疗，在人类的几个I/II/III期临床试验中。然而，这些试验中没有一项涉及血友病儿童，因为传统的肝脏导向AAV基因治疗方法不适用于这些患者，原因如下：(I)直到10-12岁，肝脏仍在生长和分裂，且每次细胞分裂时，AAV载体基因组因其同源性质而被稀释；(Ii)将需要重复基因输送，但重复给药不是理想的AAV载体，因为在第一次注射后已存在针对AAV载体的抗体。在此，我们描述了一种优化的人凝血因子IX(hF.IX)基因表达盒的研制，它是在人肝特异性转甲状腺激素启动子(optNE-ttr-hF.ix)的控制下开发的，该启动子与无开放末端的AAV反向末端重复序列(ITR)共价连接，在人肝癌细胞中的hF.IX表达水平比线性ttR-hF.IX DNA构建体高约6倍。在未来的研究中，将optNE-TTR-hF.IX DNA包埋在肝靶向合成脂质体中，可能为儿童血友病的潜在基因治疗提供一条可行的途径。
Recombinant AAV serotype vectors and their variants have been or are currently being used for gene therapy for hemophilia in several phase I/II/III clinical trials in humans. However, none of these trials have included children with hemophilia since the traditional liver-directed AAV gene therapy will not work in these patients because of the following reasons: (i) Up until age 10–12, the liver is still growing and dividing, and with every cell division, the AAV vector genomes will be diluted out due to their episomal nature; and (ii) Repeated gene delivery will be needed, but repeat dosing, even with an ideal AAV vector is not an option because of pre-existing antibodies to AAV vectors following the first administration. Here we describe the development of an optimized human Factor IX (hF.IX) gene expression cassette under the control of a human liver-specific transthyretin promoter covalently flanked by AAV inverted terminal repeats (ITRs) with no open ends (optNE-TTR-hF.IX), which mediated ~sixfold higher hF.IX levels than that from a linear TTR-hF.IX DNA construct in human hepatoma cells up to four-weeks post-transfection. In future studies, encapsidation of the optNE-TTR-hF.IX DNA in liver-targeted synthetic liposomes, may provide a viable approach for the potential gene therapy for hemophilia in children.
登录
查看更多内容
影响因子：
--
作者：
Bijlani S;Pang KM;Sivanandam V;Singh A;Chatterjee S
通讯作者：
Chatterjee S
影响因子：
64.8
作者：
DELASALLE, H;ALTENBURGER, W;LECOCQ, JP
通讯作者：
LECOCQ, JP
影响因子：
5.4
作者：
Pereira, DJ;McCarty, DM;Muzyczka, N
通讯作者：
Muzyczka, N
影响因子：
10.4
作者：
Makris, M.;Oldenburg, J.;Fijnvandraat, K.
通讯作者：
Fijnvandraat, K.
DOI：
10.1038/mtna.2014.16
发表时间：
2014-05-27
期刊：
Molecular therapy. Nucleic acids
影响因子：
--
作者：
通讯作者：
--