Novel Approaches for the Treatment of Familial Hypercholesterolemia: Current Status and Future Challenges.
Novel Approaches for the Treatment of Familial Hypercholesterolemia: Current Status and Future Challenges.
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治疗家族性高胆固醇血症的新方法：现状和未来的挑战
DOI：
10.5551/jat.43372
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发表时间：
2018-08-01
影响因子：
4.4
通讯作者：
Cheng XS
中科院分区：
文献类型：
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作者：
Jiang L;Wang LY;Cheng XS
家族性高胆固醇血症 (FH) 是一种常染色体显性遗传疾病，其特征是血浆低密度脂蛋白胆固醇 (LDL-c) 水平升高和心血管疾病风险增加。尽管使用高剂量他汀类药物以及最近添加前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂作为治疗选择，但许多纯合子 FH 患者未能实现 LDL-c 水平的最佳降低。基因治疗已成为当代生命科学最有前途的研究方向之一，也是FH潜在的治疗选择。最近的研究证实了表达人LDL-c受体基因的重组腺相关病毒8载体在小鼠模型中的功效，并且该载体目前正在进行2期临床试验。基于反义寡核苷酸和小干扰RNA的基因治疗领域也取得了很大进展，目前正在进行1-2期临床试验。此外，使用小环DNA载体、microRNA、长链非编码RNA和CRISPR/Cas9基因编辑系统等新方法已显示出FH治疗的巨大潜力。然而，基因疗法的递送系统、免疫原性、准确性和特异性限制了其临床应用。在本文中，我们讨论基因治疗的现状以及可能影响基因治疗治疗 FH 临床应用的最新进展。
Familial hypercholesterolemia (FH) is an autosomal-dominant disorder that is characterized by high plasma lowdensity lipoprotein cholesterol (LDL-c) levels and an increased risk of cardiovascular disease. Despite the use of high-dose statins and the recent addition of proprotein convertase subtilisin/kexin type 9 inhibitors as a treatment option, many patients with homozygous FH fail to achieve optimal reductions of LDL-c levels. Gene therapy has become one of the most promising research directions for contemporary life sciences and is a potential treatment option for FH. Recent studies have confirmed the efficacy of a recombinant adeno-associated virus 8 vector expressing the human LDL-c receptor gene in a mouse model, and this vector is currently in phase 2 clinical trials. Much progress has also been achieved in the fields of antisense oligonucleotide- and small interfering RNA-based gene therapies, which are in phase 1–2 clinical trials. In addition, novel approaches, such as the use of minicircle DNA vectors, microRNAs, long non-coding RNAs, and the CRISPR/Cas9 gene-editing system, have shown great potential for FH therapy. However, the delivery system, immunogenicity, accuracy, and specificity of gene therapies limit their clinical applications. In this article, we discuss the current status of gene therapy and recent advances that will likely affect the clinical application of gene therapy for the treatment of FH.