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首页> 外文期刊>Scientific reports. >Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes
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Plasmid DNA gene therapy of the Niemann-Pick C1 mouse with transferrin receptor-targeted Trojan horse liposomes

机译：具有转铁蛋白受体 - 靶向特洛伊木马脂质体的Niemann-pick C1小鼠的质粒DNA基因治疗

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Niemann-Pick C1 (NPC1) is a lysosomal cholesterol storage disorder, that severely affects the brain, and is caused by mutations in the NPC1 gene, which encodes an intracellular membrane transporter of non-esterified cholesterol. Therapeutic options for NPC1 are few, and classical enzyme replacement therapy with the recombinant protein is not possible as the NPC1 gene product is an insoluble membrane protein, which increases the need for development of gene therapy for NPC1. While viral based gene therapy is under development, it is important to investigate alternative approaches to brain gene therapy without viral vectors. The present work develops a plasmid DNA approach to gene therapy of NPC1 using Trojan horse liposomes (THLs), wherein the plasmid DNA is encapsulated in 100?nm pegylated liposomes, which are targeted to organs with a monoclonal antibody against the mouse transferrin receptor. THLs were encapsulated with a 8.0?kb plasmid DNA encoding the 3.9?kb human NPC1 open reading frame, under the influence of a 1.5?kb platelet derived growth factor B (PDGFB) promoter. THLs were administered weekly beginning at 6–7?weeks in the NPC1?/? null mouse, and delivery of the plasmid DNA, and NPC1 mRNA expression in brain, spleen, and liver were confirmed by quantitative PCR. THL treatment reduced tissue inclusion bodies in brain, and peripheral organs, but did not prolong lifespan in these mice. The work suggests that early treatment after birth may be required to reverse this disease model with NPC1 gene replacement therapy.
机译：Niemann-Pick C1（NPC1）是一种溶酶体胆固醇储存障碍，其严重影响大脑，并且是由NPC1基因的突变引起的，其编码非酯化胆固醇的细胞内膜转运蛋白。 NPC1的治疗选择很少，并且随着NPC1基因产物是一种不溶性膜蛋白，不可能具有重组蛋白的典型酶替代疗法，这增加了对NPC1的基因治疗的发展需求。虽然存在基于病毒的基因治疗，但重要的是要在没有病毒载体的情况下调查脑基因治疗的替代方法。本作者使用特洛伊木马脂质体（THL）制定了对NPC1基因治疗的质粒DNA方法，其中质粒DNA被包封在100μmPEG化脂质体中，其靶向与小鼠转移素受体的单克隆抗体的器官。将THLS与编码3.9？KB人NPC1开放阅读框的8.0 kB质粒DNA包装，在1.5Ω血小板衍生生长因子B（PDGFB）启动子的影响下。 THLS每周一次从6-7左右给药？在NPC1中的几周？/？通过定量PCR证实了脑，脾脏和肝脏中的质粒DNA和NPC1 mRNA表达的NULL鼠标和递送NPC1 mRNA表达。 THL治疗减少了脑中的组织包涵体，外周器官，但在这些小鼠中没有延长寿命。该作品表明，可能需要早期治疗后逆转该疾病模型与NPC1基因替代疗法。

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