Adeno-Associated Virus Serotype 8 Gene Therapy Leads to Significant Lowering of Plasma Cholesterol Levels in Humanized Mouse Models of Homozygous and Heterozygous Familial Hypercholesterolemia
Adeno-Associated Virus Serotype 8 Gene Therapy Leads to Significant Lowering of Plasma Cholesterol Levels in Humanized Mouse Models of Homozygous and Heterozygous Familial Hypercholesterolemia
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DOI：
10.1089/hum.2012.108
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发表时间：
2013-01-01
影响因子：
4.2
通讯作者：
Rader, Daniel J.
中科院分区：
文献类型：
--
作者：
Kassim, Sadik H.;Li, Hui;Rader, Daniel J.
家族性高胆固醇血症(FH)是一种由低密度脂蛋白受体(LDLR)编码基因突变引起的危及生命的遗传性疾病。作为临床试验的桥梁，我们建立了一个缺乏LDLR和载脂蛋白B(ApoB)mRNA编辑催化多肽-1(APOBEC-1)并表达人ApoB100转基因的“人源化”小鼠模型，以允许更真实地模拟临床转基因产物人LDLR(HLDLR)及其内源性配体人ApoB100之间的体内相互作用。在饮食中，人源化的低密度脂蛋白受体缺陷小鼠有实质性的高胆固醇血症，并且与先前的FH小鼠模型相比，其脂蛋白表型更接近于人类纯合FH(HoFH)。在注射编码人低密度脂蛋白受体基因的8型腺相关病毒(AAV8)载体后，低至1.5×10(11)基因组拷贝(GC)/kg的剂量可显著纠正高胆固醇血症。考虑到一些杂合性FH(HeFH)患者不能用目前的治疗方法充分治疗，我们随后将我们的研究扩展到类似的“人源化”小鼠，这些小鼠是LDLR缺乏的杂合子，并且具有与杂合性FH相似的脂蛋白表型。注射AAV8-hLDLR可显著降低血清总胆固醇和低密度脂蛋白胆固醇(5×10(11)gC/kg)。总而言之，这些数据证明了肝脏特异性AAV8-hLDLR载体在治疗同时建模HoFH和HeFH的人源化小鼠方面的安全性和有效性。
Familial hypercholesterolemia (FH) is a life-threatening genetic disease caused by mutations in the gene encoding low-density lipoprotein receptor (LDLR). As a bridge to clinical trials, we generated a "humanized" mouse model lacking LDLR and apolipoprotein B (ApoB) mRNA editing catalytic polypeptide-1 (APOBEC-1) expression and expressing a human ApoB100 transgene in order to permit more authentic simulation of in vivo interactions between the clinical transgene product, human LDLR (hLDLR), and its endogenous ligand, human ApoB100. On a chow diet, the humanized LDLR-deficient mice have substantial hypercholesterolemia and a lipoprotein phenotype more closely resembling human homozygous FH (hoFH) than in previous mouse models of FH. On injection of an adeno-associated virus serotype 8 (AAV8) vector encoding the human LDLR cDNA, significant correction of hypercholesterolemia was realized at doses as low as 1.5 x 10(11) genome copies (GC)/kg. Given that some patients with heterozygous FH (heFH) cannot be adequately treated with current therapy, we then extended our studies to similarly "humanized" mice that were heterozygous for LDLR deficiency, and that have a lipoprotein phenotype resembling heterozygous FH. Injection of AAV8-hLDLR brought about significant reduction in total and LDL cholesterol at doses as low as 5 x 10(11) GC/kg. Collectively, these data demonstrate the safety and efficacy of the liver-specific AAV8-hLDLR vector in the treatment of humanized mice modeling both hoFH and heFH.