-Acetylgalactosamine (GalNAc)-conjugated small interfering RNA (siRNA) therapies have received approval for treating both orphan and prevalent diseases. To improve efficacy and streamline the chemical synthesis process for efficient and cost-effective manufacturing, we conducted this study to identify better designs of GalNAc-siRNA conjugates for therapeutic development. Here, we present data on redesigned GalNAc-based ligands conjugated with siRNAs against angiopoietin-like 3 (ANGPTL3) and lipoprotein (a) (Lp(a)), two target molecules with the potential to address large unmet medical needs in atherosclerotic cardiovascular diseases. By attaching a novel pyran-derived scaffold to serial monovalent GalNAc units before solid-phase oligonucleotide synthesis, we achieved increased GalNAc-siRNA production efficiency with fewer synthesis steps compared to the standard triantennary GalNAc construct L96. The improved GalNAc-siRNA conjugates demonstrated equivalent or superior efficacy compared to triantennary GalNAc-conjugated siRNAs.

中文翻译：

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改进的 GalNAc 缀合在开发针对心血管疾病的经济有效的 siRNA 疗法中的应用

-乙酰半乳糖胺 (GalNAc) 结合的小干扰 RNA (siRNA) 疗法已获得批准用于治疗孤儿疾病和流行疾病。为了提高功效并简化化学合成工艺，实现高效且经济高效的制造，我们进行了这项研究，以确定用于治疗开发的 GalNAc-siRNA 缀合物的更好设计。在这里，我们展示了重新设计的基于 GalNAc 的配体与针对血管生成素样 3 (ANGPTL3) 和脂蛋白 (a) (Lp(a)) 的 siRNA 缀合的数据，这两种目标分子有可能解决动脉粥样硬化性心血管疾病中大量未满足的医疗需求。通过在固相寡核苷酸合成之前将新型吡喃衍生支架连接到一系列单价 GalNAc 单元，与标准三触角 GalNAc 构建体 L96 相比，我们以更少的合成步骤实现了 GalNAc-siRNA 生产效率的提高。与三触角 GalNAc 缀合的 siRNA 相比，改进的 GalNAc-siRNA 缀合物表现出同等或更好的功效。