In utero nanoparticle delivery for site-specific genome editing.
In utero nanoparticle delivery for site-specific genome editing.
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DOI：
10.1038/s41467-018-04894-2
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发表时间：
2018-06-26
影响因子：
16.6
通讯作者：
Saltzman WM
中科院分区：
文献类型：
--
作者：
Ricciardi AS;Bahal R;Farrelly JS;Quijano E;Bianchi AH;Luks VL;Putman R;López-Giráldez F;Coşkun S;Song E;Liu Y;Hsieh WC;Ly DH;Stitelman DH;Glazer PM;Saltzman WM
遗传性疾病可以在怀孕早期诊断，但许多单基因疾病继续造成相当大的新生儿和儿科发病率和死亡率。然而，通过子宫内基因编辑进行早期干预可以纠正遗传缺陷，可能允许正常器官发育，功能性疾病改善或治愈。在这里，我们证明了安全的静脉内和羊膜内给药的聚合物纳米粒子的胎儿小鼠组织在选定的胎龄，对生存或出生后的生长没有影响。在子宫内引入含有肽核酸（PNA）和供体DNA的纳米颗粒纠正了人类β-地中海贫血小鼠模型中β-珠蛋白基因的致病突变，使出生后血液血红蛋白水平持续升高至正常范围，网织红细胞计数减少，脾肿大逆转，存活率提高，在部分同源基因座中未检测到脱靶突变。这项工作可能为人类单基因疾病的胎儿基因编辑的安全和通用方法提供基础。在子宫内纠正遗传缺陷可以改善基因治疗的结果。在这里，作者证明了将纳米颗粒安全递送到胎儿小鼠组织，并表明含有肽核酸的纳米颗粒编辑β-珠蛋白基因在β-地中海贫血小鼠模型中是有效的。
Genetic diseases can be diagnosed early during pregnancy, but many monogenic disorders continue to cause considerable neonatal and pediatric morbidity and mortality. Early intervention through intrauterine gene editing, however, could correct the genetic defect, potentially allowing for normal organ development, functional disease improvement, or cure. Here we demonstrate safe intravenous and intra-amniotic administration of polymeric nanoparticles to fetal mouse tissues at selected gestational ages with no effect on survival or postnatal growth. In utero introduction of nanoparticles containing peptide nucleic acids (PNAs) and donor DNAs corrects a disease-causing mutation in the β-globin gene in a mouse model of human β-thalassemia, yielding sustained postnatal elevation of blood hemoglobin levels into the normal range, reduced reticulocyte counts, reversal of splenomegaly, and improved survival, with no detected off-target mutations in partially homologous loci. This work may provide the basis for a safe and versatile method of fetal gene editing for human monogenic disorders. The correction of genetic defects in utero could allow for improved outcomes of gene therapy. Here, the authors demonstrate safe delivery of nanoparticles to fetal mouse tissues, and show that nanoparticles containing peptide nucleic acids to edit the beta-globin gene are effective in a mouse model of beta-thalassemia.
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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.
DOI：
10.1002/cbic.200800441
发表时间：
2008-10-13
期刊：
Chembiochem : a European journal of chemical biology
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
HANVEY, JC;PEFFER, NJ;BABISS, LE
通讯作者：
BABISS, LE
影响因子：
3.2
作者：
Bahal, Raman;Sahu, Bichismita;Rapireddy, Srinivas;Lee, Chong-Min;Ly, Danith H.
通讯作者：
Ly, Danith H.
影响因子：
158.5
作者：
Hacein-Bey-Abina, S;Le Deist, F;Leiva, L
通讯作者：
Leiva, L