首次体内碱基编辑降低胆固醇

IF 33.1 1区 生物学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Nature biotechnology Pub Date : 2023-12-11 DOI:10.1038/s41587-023-02070-6
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引用次数: 0

摘要

首例 "一次性 "体内碱基编辑药物使低密度脂蛋白胆固醇(LDL-c)基因水平高的人的胆固醇降低率达到剂量依赖性水平。Verve Therapeutics 公司公布了一项 1b 期临床试验的概念验证数据,该试验旨在测试 VERVE-101 这种单疗程体内碱基编辑疗法能否通过使肝脏中的丙蛋白转化酶 PCSK9 酶基因失活来持久降低血液中的胆固醇。对动脉粥样硬化性心脏病有天然抵抗力的人体内的 PCSK9 基因会发生罕见的失活突变,而杂合子家族性高胆固醇血症患者体内的 PCSK9 基因则会永久开启。在美国心脏协会的会议上,报告了对 10 名平均低密度脂蛋白胆固醇(LDL-c)为 193 毫克/分升的参与者进行治疗的第一阶段中期结果。接受最高剂量(0.6 毫克/千克体重)治疗的患者的低密度脂蛋白胆固醇降低了 55%,并在 6 个月后得以维持;接受 0.45 毫克/千克治疗的两名患者的低密度脂蛋白胆固醇降低了 39-48%。但该试验也凸显了可能存在的安全性问题,因为一名患者发生了非致命性心脏骤停,这可能与治疗有关。鉴于目前已有药理 PCSK9 抑制剂,有人担心基因编辑方法存在风险。赛诺菲公司(Sanofi)和再生元公司(Regeneron)生产的单克隆抗体 Praluent(alirocumab)、安进公司(Amgen)生产的 Repatha(evolocumab)以及诺华公司(Novartis)生产的 siRNA Leqvio(inclisiran)都能将家族性高胆固醇血症患者的低密度脂蛋白胆固醇降低约 50%。不过,与传统的 CRISPR-Cas 技术相比,碱基编辑技术不会造成双链断裂,因此发生意外基因组重排的可能性较小。VERVE-101 由腺嘌呤脱氨酶 mRNA 与催化受损的 Cas9 切口酶和靶向 PCSK9 的引导 RNA 共价连接组成,包含在一个工程化的脂质纳米粒子中。腺嘌呤脱氨酶会在靶位点产生 A-T 到 G-C 的突变。VERVE-101 的试验仍在继续。Verve 还计划对另一种腺嘌呤碱基编辑 mRNA 加 gRNA 包装在 N-乙酰半乳糖胺脂质纳米粒子中进行试验,以关闭同型高胆固醇血症患者的肝 ANGPTL3 基因。
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来源期刊
Nature biotechnology
Nature biotechnology 工程技术-生物工程与应用微生物
CiteScore
63.00
自引率
1.70%
发文量
382
审稿时长
3 months
期刊介绍: Nature Biotechnology is a monthly journal that focuses on the science and business of biotechnology. It covers a wide range of topics including technology/methodology advancements in the biological, biomedical, agricultural, and environmental sciences. The journal also explores the commercial, political, ethical, legal, and societal aspects of this research. The journal serves researchers by providing peer-reviewed research papers in the field of biotechnology. It also serves the business community by delivering news about research developments. This approach ensures that both the scientific and business communities are well-informed and able to stay up-to-date on the latest advancements and opportunities in the field. Some key areas of interest in which the journal actively seeks research papers include molecular engineering of nucleic acids and proteins, molecular therapy, large-scale biology, computational biology, regenerative medicine, imaging technology, analytical biotechnology, applied immunology, food and agricultural biotechnology, and environmental biotechnology. In summary, Nature Biotechnology is a comprehensive journal that covers both the scientific and business aspects of biotechnology. It strives to provide researchers with valuable research papers and news while also delivering important scientific advancements to the business community.
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