Exon skipping of hepatic APOB pre-mRNA with splice-switching oligonucleotides reduces LDL cholesterol in vivo.
Exon skipping of hepatic APOB pre-mRNA with splice-switching oligonucleotides reduces LDL cholesterol in vivo.
复制标题
DOI：
10.1038/mt.2012.264
复制
发表时间：
2013-03
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
家族性高胆固醇血症（FH）是一种遗传性疾病，其特征是由于LDL受体-载脂蛋白B（APOB）结合缺陷导致血浆低密度脂蛋白（LDL）水平极高。目前的治疗方法，如他汀类药物或低密度脂蛋白单采术纯合子FH是不够有效的降低低密度脂蛋白胆固醇或昂贵。针对LDL颗粒的结构蛋白APOB 100的治疗是FH的潜在疗法。我们已经开发了一系列APOB指导的剪接转换寡核苷酸（SSO），导致APOB 87，APOB 100的截短亚型的表达。APOB 87，类似于在具有不同病症（家族性低β脂蛋白血症）的患者中表达的截短同种型，通过抑制VLDL组装和增加LDL清除来降低LDL胆固醇。我们证明，这些“APO跳跃”SSO诱导高水平的外显子跳跃和表达的APOB 87亚型，但基本上不抑制APOB 48在细胞系中的表达。将优化的APO-skip SSO单次注射到人APOB转基因小鼠中导致大量外显子跳跃，持续超过6天。每周一次的治疗使这些小鼠的LDL胆固醇水平持续降低34-51%，在头对头比较中上级优于普伐他汀。这些结果验证了APO跳过SSO作为FH的候选疗法。
Familial hypercholesterolemia (FH) is a genetic disorder characterized by extremely high levels of plasma low-density lipoprotein (LDL), due to defective LDL receptor-Apolipoprotein B (APOB) binding. Current therapies such as statins or LDL apheresis for homozygous FH are insufficiently efficacious at lowering LDL cholesterol or are expensive. Treatments that target APOB100, the structural protein of LDL particles, are potential therapies for FH. We have developed a series of APOB-directed splice-switching oligonucleotides (SSOs) that cause the expression of APOB87, a truncated isoform of APOB100. APOB87, like similarly truncated isoforms expressed in patients with a different condition, familial hypobetalipoproteinemia, lowers LDL cholesterol by inhibiting VLDL assembly and increasing LDL clearance. We demonstrate that these “APO-skip” SSOs induce high levels of exon skipping and expression of the APOB87 isoform, but do not substantially inhibit APOB48 expression in cell lines. A single injection of an optimized APO-skip SSO into mice transgenic for human APOB resulted in abundant exon skipping that persists for more than 6 d. Weekly treatments generated a sustained reduction in LDL cholesterol levels of 34-51% in these mice, superior to Pravastatin in a head-to-head comparison. These results validate APO-skip SSOs as a candidate therapy for FH.
登录
查看更多内容
影响因子：
14.9
作者：
Straarup EM;Fisker N;Hedtjärn M;Lindholm MW;Rosenbohm C;Aarup V;Hansen HF;Ørum H;Hansen JB;Koch T
通讯作者：
Koch T
DOI：
10.1073/pnas.94.6.2620
发表时间：
1997-03-18
影响因子：
11.1
作者：
Agrawal, S;Jiang, ZW;Zhang, RW
通讯作者：
Zhang, RW
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
168.9
作者：
Raal, Frederick J.;Santos, Raul D.;Crooke, Stanley T.
通讯作者：
Crooke, Stanley T.
影响因子：
8.7
作者：
Gabelli, C;Bilato, C;Baggio, G
通讯作者：
Baggio, G