Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing.
Dose-Dependent Prevention of Metabolic and Neurologic Disease in Murine MPS II by ZFN-Mediated In Vivo Genome Editing.
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DOI：
10.1016/j.ymthe.2018.03.002
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发表时间：
2018-04-04
期刊：
影响因子：
--
通讯作者：
McIvor RS
中科院分区：
文献类型：
--
作者：
Laoharawee K;DeKelver RC;Podetz-Pedersen KM;Rohde M;Sproul S;Nguyen HO;Nguyen T;St Martin SJ;Ou L;Tom S;Radeke R;Meyer KE;Holmes MC;Whitley CB;Wechsler T;McIvor RS
粘多糖症II型(MPS II)是一种X连锁的隐性溶酶体疾病，由艾杜酸2-硫酸酯酶(IDs)缺乏引起，导致糖胺多糖(GAG)在患者组织中积聚，进展性疾病，寿命缩短。目前可用的酶替代疗法(ERT)需要终生输液，并且不能提供神经益处。我们利用锌指核酸酶(ZFN)靶向系统来介导基因组编辑，以将人类入侵检测系统(HIDs)编码序列插入到MPS II小鼠模型肝细胞白蛋白基因座内含子1的“安全港”位置。将编码一对ZFN的重组AAV2/8载体和一个HIDS基因供体分别系统地注射于MPS II小鼠体内。在ZFN+供体处理的小鼠的循环和外周器官中，观察到超生理学的、载体剂量依赖的IDS酶水平。所有ZFN+供体处理组的组织中GAG含量均显著降低。令人惊讶的是，我们还证明了ZFN介导的基因组编辑防止了以高载体剂量水平治疗的年轻MPS II小鼠(6-9周大)的神经认知缺陷的发展。我们的结论是，这个基于ZFN的白蛋白基因治疗性蛋白表达平台是治疗MPS II和其他溶酶体疾病的一种有前途的方法。AAV介导的ZFN和IDS供体体内递送导致了MPS II小鼠模型中位置特异的基因插入和剂量依赖的IDS表达。这些结果支持了目前正在进行的临床试验，这是有史以来第一次进行体内人类基因组编辑研究。
Mucopolysaccharidosis type II (MPS II) is an X-linked recessive lysosomal disorder caused by deficiency of iduronate 2-sulfatase (IDS), leading to accumulation of glycosaminoglycans (GAGs) in tissues of affected individuals, progressive disease, and shortened lifespan. Currently available enzyme replacement therapy (ERT) requires lifelong infusions and does not provide neurologic benefit. We utilized a zinc finger nuclease (ZFN)-targeting system to mediate genome editing for insertion of the human IDS (hIDS) coding sequence into a “safe harbor” site, intron 1 of the albumin locus in hepatocytes of an MPS II mouse model. Three dose levels of recombinant AAV2/8 vectors encoding a pair of ZFNs and a hIDS cDNA donor were administered systemically in MPS II mice. Supraphysiological, vector dose-dependent levels of IDS enzyme were observed in the circulation and peripheral organs of ZFN+donor-treated mice. GAG contents were markedly reduced in tissues from all ZFN+donor-treated groups. Surprisingly, we also demonstrate that ZFN-mediated genome editing prevented the development of neurocognitive deficit in young MPS II mice (6–9 weeks old) treated at high vector dose levels. We conclude that this ZFN-based platform for expression of therapeutic proteins from the albumin locus is a promising approach for treatment of MPS II and other lysosomal diseases. AAV-mediated in vivo delivery of ZFN and IDS donor resulted in site-specific gene insertion and dose-dependent IDS expression in a mouse model of MPS II. These results support a currently open clinical trial, the first ever in vivo human genome editing study to be conducted.
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影响因子：
64.8
作者：
Barzel, A.;Paulk, N. K.;Shi, Y.;Huang, Y.;Chu, K.;Zhang, F.;Valdmanis, P. N.;Spector, L. P.;Porteus, M. H.;Gaensler, K. M.;Kay, M. A.
通讯作者：
Kay, M. A.
影响因子：
64.8
作者：
Genovese, Pietro;Schiroli, Giulia;Escobar, Giulia;Di Tomaso, Tiziano;Firrito, Claudia;Calabria, Andrea;Moi, Davide;Mazzieri, Roberta;Bonini, Chiara;Holmes, Michael C.;Gregory, Philip D.;van der Burg, Mirjam;Gentner, Bernhard;Montini, Eugenio;Lombardo, Angelo;Naldini, Luigi
通讯作者：
Naldini, Luigi
影响因子：
12.4
作者：
Matzner, Ulrich;Luellmann-Rauch, Renate;Gieselmann, Volkmar
通讯作者：
Gieselmann, Volkmar
DOI：
10.1073/pnas.94.4.1287
发表时间：
1997-02-18
影响因子：
11.1
作者：
Ohashi, T;Watabe, K;Eto, Y
通讯作者：
Eto, Y
影响因子：
3.8
作者：
Ou, Li;Herzog, Tyler;Whitley, Chester B.
通讯作者：
Whitley, Chester B.