Background
原发性血脂异常是一种遗传代谢疾病，其特征在于五个主要类别的胆固醇，甘油三酸酯（TG）和脂蛋白构成的脂质谱的异常：乳清细胞，乳糜密度脂蛋白（VLDL），中间密度的脂蛋白（IDL），乳糜密度的脂蛋白（VLDL），IDL），脂肪蛋白（VLDL），中等密度的脂蛋白（IDL），IDL），，中等密度。低密度脂蛋白（LDL）和高密度脂蛋白（HDL）。脂蛋白和脂质代谢的失调是动脉粥样硬化和冠状动脉疾病发展的最大因素。
一些单独使用标准他汀类药物疗法或与其他脂质降低疗法结合使用的患者无法实现其LDL胆固醇（LDL-C）降低目标，尤其是家族性高胆固醇血症的患者。因此，有效的治疗选择是有效的治疗选择，需要为这些患者提供替代和辅助治疗策略，并通过反义寡核苷酸（ASO）和小型干扰RNA（siRNA）进行替代和辅助治疗策略。
Familial hypercholesterolemia is caused by mutations in the following three genes relevant to plasma LDL metabolism: low-density lipoprotein cholesterol receptor (LDLR), apolipoprotein B100 (ApoB-100) and proprotein convertase subtilisin/kexin type 9 (PCSK9). Because gene silencing achieves inhibition of the production of selected proteins, specific therapies have been developed exploiting the target biology and knowledge of the lipid metabolism underlying the disorder. The targets investigated thus far, and the antisense therapies developed against these targets according to Pipeline Intelligence will be reviewed.
Targets of antisense therapies in lipid disorders
APOB-100
APOB-100is an essential protein for the production of pro-atherogenic lipoproteins, namely VLDL, LDL and lipoprotein A. High levels of ApoB-100, especially associated with the higher LDL levels, is a primary driver for cardiovascular disease.
apo（a）
Apolipoprotein (a) [Apo(a)] which is bound to ApoB-100 via a disulfide bond, leads to the formation of lipoprotein (a) [Lp(a)], a cholesterol-rich LDL-like particle. Lp(a) is a key driver for cardiovascular disease due to its association with an increased risk of coronary heart disease. Therefore, drugs that can lower Lp(a) levels by targeting Apo(a) are being developed.
apociii
Apolipoprotein CIII (ApoCIII) is a 79-amino acid glycoprotein synthesized in the liver that has a role in the regulation of TG levels. ApoCIII is present on TG rich lipoproteins, such as VLDL. ApoCIII impairs clearance of these particles by inhibition of the enzyme lipoprotein lipase (LPL). It is also known to delay clearance of TG-rich lipoproteins. ApoCIII may also play a role in the activity of hepatic lipase and assembly and secretion of TG-rich lipoproteins. Therefore, ApoCIII plays a key role directly and indirectly in the pathogenesis of atherosclerosis and is being explored as a therapeutic target for hypertriglyceridemia.
PCSK9
PCSK9促进LDL受体的降解，从而增加血清中LDL-C的水平，并最终增加心血管疾病。相反，功能丧失突变伴随着LDL-C水平降低，心血管疾病的风险降低。
ANGPTL3
Angiopoietin-like 3 protein (ANGPTL3) is a liver synthesized inhibitor of lipoprotein lipase and endothelial lipase. ANGPTL3 inhibition has been shown to lower serum LDL, serum and liver TG levels.
The landscape of antisense therapies for lipid disorders according to Pipeline Intelligence is presented in Figure 1.
结论
Despite the use of first-line statin therapy, many patients with familial hypercholesterolemia fail to achieve optimal reductions of LDL-C levels or are unable to tolerate statins. ASOs and siRNAs have proven to be effective as adjunct or alternate therapies in these patients.
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