美国杰克逊维尔临床研究中心Michael J. Koren等研究人员完成新型siRNA靶向脂蛋白a的临床前开发和1期试验。相关论文于2022年1月13日在线发表在《自然—医学》杂志上。

Author: Koren, Michael J., Moriarty, Patrick Maurice, Baum, Seth J., Neutel, Joel, Hernandez-Illas, Martha, Weintraub, Howard S., Florio, Monica, Kassahun, Helina, Melquist, Stacey, Varrieur, Tracy, Haldar, Saptarsi M., Sohn, Winnie, Wang, Huei, Elliott-Davey, Mary, Rock, Brooke M., Pei, Tao, Homann, Oliver, Hellawell, Jennifer, Watts, Gerald F.

Issue&Volume: 2022-01-13

Abstract: Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5–8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71–97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

DOI: 10.1038/s41591-021-01634-w

Source: https://www.nature.com/articles/s41591-021-01634-w