In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery.
In vivo correction of anaemia in β-thalassemic mice by γPNA-mediated gene editing with nanoparticle delivery.
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DOI：
10.1038/ncomms13304
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发表时间：
2016-10-26
影响因子：
16.6
通讯作者：
Glazer, Peter M.
中科院分区：
文献类型：
--
作者：
Bahal, Raman;McNeer, Nicole Ali;Quijano, Elias;Liu, Yanfeng;Sulkowski, Parker;Turchick, Audrey;Lu, Yi-Chien;Bhunia, Dinesh C.;Manna, Arunava;Greiner, Dale L.;Brehm, Michael A.;Cheng, Christopher J.;Lopez-Giraldez, Francesc;Ricciardi, Adele;Beloor, Jagadish;Krause, Diane S.;Kumar, Priti;Gallagher, Patrick G.;Braddock, Demetrios T.;Saltzman, W. Mark;Ly, Danith H.;Glazer, Peter M.
这种血液疾病，β-地中海贫血，被认为是基因校正的一个有吸引力的目标。位点特异性三联体的形成已被证明可以诱导DNA修复，从而催化基因组编辑。在这里，我们报告了在γ位置取代的三联体形成肽核酸（PNAs）加上干细胞因子(SCF)/c-Kit途径的刺激，在人类β-地中海贫血小鼠模型中的造血干细胞（hsc）中产生了高水平的基因编辑。向地中海贫血小鼠注射SCF和含有γ - pnas和供体dna的纳米颗粒可改善疾病表型，使血红蛋白水平持续升高至正常范围，网状细胞增多症减少，脾大逆转，造血干细胞中高达7%的β-珠蛋白基因校正，脱靶效应极低。纳米颗粒输送、下一代γ - pnas和SCF治疗的结合，可能为血液遗传疾病提供一种微创治疗，这种治疗可以通过静脉注射安全而简单地实现。基因编辑方法被广泛用于纠正突变，但它们的应用在很大程度上仅限于细胞，而不是活体动物。在这里，作者表明，体内γ pna介导的β-珠蛋白突变的编辑可由SCF促进，并导致β-地中海贫血小鼠血红蛋白水平的持续正常化。
The blood disorder, β-thalassaemia, is considered an attractive target for gene correction. Site-specific triplex formation has been shown to induce DNA repair and thereby catalyse genome editing. Here we report that triplex-forming peptide nucleic acids (PNAs) substituted at the γ position plus stimulation of the stem cell factor (SCF)/c-Kit pathway yielded high levels of gene editing in haematopoietic stem cells (HSCs) in a mouse model of human β-thalassaemia. Injection of thalassemic mice with SCF plus nanoparticles containing γPNAs and donor DNAs ameliorated the disease phenotype, with sustained elevation of blood haemoglobin levels into the normal range, reduced reticulocytosis, reversal of splenomegaly and up to 7% β-globin gene correction in HSCs, with extremely low off-target effects. The combination of nanoparticle delivery, next generation γPNAs and SCF treatment may offer a minimally invasive treatment for genetic disorders of the blood that can be achieved safely and simply by intravenous administration. Gene editing approaches are widely used for correcting mutations, but their application is largely limited to cells and not living animals. Here the authors show that in vivo γPNA-mediated editing of a β-globin mutation is promoted by SCF and leads to sustained normalization of blood haemoglobin levels β-thalassemic mice.
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影响因子：
10
作者：
Fields RJ;Quijano E;McNeer NA;Caputo C;Bahal R;Anandalingam K;Egan ME;Glazer PM;Saltzman WM
通讯作者：
Saltzman WM
在气道上皮中提供三肽核酸分子的纳米颗粒。
影响因子：
16.6
作者：
McNeer, Nicole Ali;Anandalingam, Kavitha;Fields, Rachel J.;Caputo, Christina;Kopic, Sascha;Gupta, Anisha;Quijano, Elias;Polikoff, Lee;Kong, Yong;Bahal, Raman;Geibel, John P.;Glazer, Peter M.;Saltzman, W. Mark;Egan, Marie E.
通讯作者：
Egan, Marie E.
DOI：
10.1073/pnas.0711666105
发表时间：
2008-07-29
影响因子：
11.1
作者：
Miccio, Annarita;Cesari, Rossano;Ferrari, Giuliana
通讯作者：
Ferrari, Giuliana
DOI：
10.1073/pnas.262556899
发表时间：
2002-12-24
影响因子：
11.1
作者：
Rogers, FA;Vasquez, KM;Glazer, PM
通讯作者：
Glazer, PM
修复与三链体形成寡核苷酸相关的 DNA 损伤。
影响因子：
4.6
作者：
Chin, Joanna Y.;Glazer, Peter M.
通讯作者：
Glazer, Peter M.