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The Lancet:基因调控新药或可代替常用心脏病药物

来源:科学网 2013-10-23 12:20

胆固醇高者通常需要服用他汀类药物以降低心脏病风险,但此类药物副作用较明显。最新完成的临床试验显示,一种通过调控基因来降低胆固醇的药物同样有效,且无明显副作用。

英国盖氏医院研究人员与美国同行一起,在英国新一期《柳叶刀》杂志上报告说,一种被称为“ALN-PCS”的新药可通过干扰核糖核酸来抑制某种基因的表达,使身体清除有害胆固醇的能力恢复正常。

研究人员招募了英美两国32名18至65岁的志愿者进行了首期临床试验,结果显示,新药可将服药者的平均胆固醇水平降低40%,与他汀类药物的效用相当,并且服用新药的志愿者均未出现抗药性或明显副作用。

据介绍,目前英国有超过500万人服用他汀类降胆固醇药物,但有约五分之一的患者对这类药物有抗药性,且不少服用者产生肌肉酸痛、健忘等副作用。

研究人员说,下一步他们将开展更大规模的临床试验,重点考察服用这种新药的长期安全性及耐药性。

英国心脏基金会专家彼得·韦斯伯格说,胆固醇过高会显著增加心脏病风险,但有些病人因抗药性或副作用不能服用常规药物,这项研究再次证实,基因技术可为开发有效、低副作用的新型药物提供新希望。(生物谷Bioon.com)

生物谷推荐的英文摘要

The Lancet         doi:10.1016/S0140-6736(13)61914-5

Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial

Dr Kevin Fitzgerald PhD a , Maria Frank-Kamenetsky PhD a, Svetlana Shulga-Morskaya MSc a, Abigail Liebow BS a, Brian R Bettencourt PhD a, Jessica E Sutherland PhD a, Renta M Hutabarat PhD a, Valerie A Clausen PhD a, Verena Karsten PhD a, Jeffrey Cehelsky MBA a, Saraswathy V Nochur PhD a, Victor Kotelianski MD a, Jay Horton MD b, Timothy Mant MD c, Joseph Chiesa MD d, James Ritter MD c, Malathy Munisamy MD d, Akshay K Vaishnaw MD a, Jared A Gollob MD a, Amy Simon MD a

Background

Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to LDL receptors, leading to their degradation. Genetics studies have shown that loss-of-function mutations in PCSK9 result in reduced plasma LDL cholesterol and decreased risk of coronary heart disease. We aimed to investigate the safety and efficacy of ALN-PCS, a small interfering RNA that inhibits PCSK9 synthesis, in healthy volunteers with raised cholesterol who were not on lipid-lowering treatment.

Methods

We did a randomised, single-blind, placebo-controlled, phase 1 dose-escalation study in healthy adult volunteers with serum LDL cholesterol of 3·00 mmol/L or higher. Participants were randomly assigned in a 3:1 ratio by computer algorithm to receive one dose of intravenous ALN-PCS (with doses ranging from 0·015 to 0·400 mg/kg) or placebo. The primary endpoint was safety and tolerability of ALN-PCS. Secondary endpoints were the pharmacokinetic characteristics of ALN-PCS and its pharmacodynamic effects on PCSK9 and LDL cholesterol. Study participants were masked to treatment assignment. Analysis was per protocol and we used ANCOVA to analyse pharmacodynamic endpoint data. This trial is registered with ClinicalTrials.gov, number NCT01437059.

Findings

Of 32 participants, 24 were randomly allocated to receive a single dose of ALN-PCS (0·015 mg/kg [n=3], 0·045 mg/kg [n=3], 0·090 mg/kg [n=3], 0·150 mg/kg [n=3], 0·250 mg/kg [n=6], or 0·400 mg/kg [n=6]) and eight to placebo. The proportions of patients affected by treatment-emergent adverse events were similar in the ALN-PCS and placebo groups (19 [79%] vs seven [88%]). ALN-PCS was rapidly distributed, with peak concentration and area under the curve (0 to last measurement) increasing in a roughly dose-proportional way across the dose range tested. In the group given 0·400 mg/kg of ALN-PCS, treatment resulted in a mean 70% reduction in circulating PCSK9 plasma protein (p<0·0001) and a mean 40% reduction in LDL cholesterol from baseline relative to placebo (p<0·0001).

Interpretation

Our results suggest that inhibition of PCSK9 synthesis by RNA interference (RNAi) provides a potentially safe mechanism to reduce LDL cholesterol concentration in healthy individuals with raised cholesterol. These results support the further assessment of ALN-PCS in patients with hypercholesterolaemia, including those being treated with statins. This study is the first to show an RNAi drug being used to affect a clinically validated endpoint (ie, LDL cholesterol) in human beings.

 

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