Exosome-based Ldlr gene therapy for familial hypercholesterolemia in a mouse model.
Exosome-based Ldlr gene therapy for familial hypercholesterolemia in a mouse model.
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基于外泌体的 Ldlr 基因治疗小鼠模型中的家族性高胆固醇血症
作者：
Li Z;Zhao P;Zhang Y;Wang J;Wang C;Liu Y;Yang G;Yuan L
家族性高胆固醇血症(FH)是由于低密度脂蛋白受体(LDLR)等基因的遗传突变导致的高低密度脂蛋白(LDL)胆固醇水平。FH导致动脉粥样硬化和心血管疾病的治疗策略的开发是迫切需要的。方法：以低密度脂蛋白受体(Ldlr)缺失小鼠(Ldlr-/-小鼠)作为FH模型。在供体小鼠肝细胞(AML12)中，通过强制表达LDLR，将LDLR mRNA包裹到外体中，得到的外体称为ExoLdlr。荧光标记和成像分析外切体在体内的分布。用定量聚合酶链式反应和Western blotting分析Ldlr基因的转导效率。通过血脂和油红O染色观察ExoLdlr对Ldlr-/-小鼠的治疗作用。结果：包裹的mRNAs在受体细胞中稳定表达，并可转化为功能蛋白。尾静脉注射后，外切体主要进入肝脏，产生丰富的LDLR蛋白，与野生型小鼠的内源性表达谱相似。与对照Exosome相比，ExoLdlr处理显著减少肝脏中的脂肪沉积，并降低血清低密度脂蛋白-胆固醇水平。值得注意的是，接受ExoLdlr治疗的小鼠动脉粥样硬化斑块和炎症的数量和大小都有所减少。结论：外切体介导的Ldlr mRNA传递有效地恢复了受体的表达，治疗了Ldlr-/-小鼠的疾病。本研究为FH患者的治疗和动脉粥样硬化的管理提供了新的治疗途径。
Familial hypercholesterolemia (FH), with high LDL (low-density lipoprotein) cholesterol levels, is due to inherited mutations in genes, such as low-density lipoprotein receptor (LDLR). Development of therapeutic strategies for FH, which causes atherosclerosis and cardiovascular disease, is urgently needed. Methods: Mice with low-density lipoprotein receptor (Ldlr) deletion (Ldlr-/- mice) were used as an FH model. Ldlr mRNA was encapsulated into exosomes by forced expression of Ldlr in the donor AML12 (alpha mouse liver) cells, and the resultant exosomes were denoted as ExoLdlr. In vivo distribution of exosomes was analyzed by fluorescence labeling and imaging. The delivery efficiency of Ldlr mRNA was analyzed by qPCR and Western blotting. Therapeutic effects of ExoLdlr were examined in Ldlr-/- mice by blood lipids and Oil Red O staining. Results: The encapsulated mRNA was stable and could be translated into functional protein in the recipient cells. Following tail vein injection, exosomes were mainly delivered into the liver, producing abundant LDLR protein, resembling the endogenous expression profile in the wild-type mouse. Compared with control exosomes, ExoLdlr treatment significantly decreased lipid deposition in the liver and lowered the serum LDL-cholesterol level. Significantly, the number and size of atherosclerotic plaques and inflammation were reduced in the ExoLdlr-treated mice. Conclusions: We have shown that exosome-mediated Ldlr mRNA delivery effectively restored receptor expression, treating the disorders in the Ldlr-/- mouse. Our study provided a new therapeutic approach for the treatment of FH patients and managing atherosclerosis.
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肾素原受体抑制可重新编程肝脏脂质代谢并保护小鼠免受饮食引起的肥胖和肝脂肪变性
影响因子：
20.1
作者：
Ren L;Sun Y;Lu H;Ye D;Han L;Wang N;Daugherty A;Li F;Wang M;Su F;Tao W;Sun J;Zelcer N;Mullick AE;Danser AHJ;Jiang Y;He Y;Ruan X;Lu X
通讯作者：
Lu X
影响因子：
39.3
作者：
Nordestgaard BG;Chapman MJ;Humphries SE;Ginsberg HN;Masana L;Descamps OS;Wiklund O;Hegele RA;Raal FJ;Defesche JC;Wiegman A;Santos RD;Watts GF;Parhofer KG;Hovingh GK;Kovanen PT;Boileau C;Averna M;Borén J;Bruckert E;Catapano AL;Kuivenhoven JA;Pajukanta P;Ray K;Stalenhoef AF;Stroes E;Taskinen MR;Tybjærg-Hansen A;European Atherosclerosis Society Consensus Panel
通讯作者：
European Atherosclerosis Society Consensus Panel
影响因子：
9.7
作者：
Aqil, Farrukh;Munagala, Radha;Gupta, Ramesh C.
通讯作者：
Gupta, Ramesh C.
影响因子：
12.4
作者：
Qiu, Xiaolan;Li, Zhi;Ren, Yi
通讯作者：
Ren, Yi
影响因子：
5.3
作者：
Ferri, Nicola;Tibolla, Gianpaolo;Catapano, Alberico Luigi
通讯作者：
Catapano, Alberico Luigi