DLin-MC3-DMA 和 ALC-0315 将 siRNA 递送至肝细胞和肝星状细胞的比较,Molecular Pharmaceutics

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DLin-MC3-DMA 和 ALC-0315 将 siRNA 递送至肝细胞和肝星状细胞的比较
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2022-05-31 , DOI: 10.1021/acs.molpharmaceut.2c00033
Francesca Ferraresso ₁ , Amy W Strilchuk ₁ , Lih Jiin Juang ₁ , Lauren G Poole ₂ , James P Luyendyk ₂ , Christian J Kastrup _{1,

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Affiliation

可电离的阳离子脂质对于体内有效发挥作用至关重要通过脂质纳米颗粒 (LNP) 递送 RNA。DLin-MC3-DMA (MC3)、ALC-0315 和 SM-102 是目前临床批准用于 RNA 治疗的唯一可电离阳离子脂质。ALC-0315 和 SM-102 是 SARS-CoV-2 mRNA 疫苗中使用的结构相似的脂质，而 MC3 用于 siRNA 疗法，以敲低肝细胞中的转甲状腺素蛋白。肝细胞和肝星状细胞 (HSC) 是 RNA 治疗特别有吸引力的靶标，因为它们合成许多血浆蛋白，包括影响凝血的蛋白。虽然 LNP 优先在肝脏中积累，但评估不同的可电离阳离子脂质将 RNA 货物输送到不同细胞群的能力对于设计肝毒性最小的 RNA-LNP 疗法非常重要。这里，我们直接将含有 ALC-0315 或 MC3 的 LNP 与肝细胞中的敲低凝血因子 VII (FVII) 和 HSC 中的 ADAMTS13 进行比较。在小鼠中，在 1 mg/kg siRNA 剂量下，与含有 MC3 的 LNP 相比，含有 ALC-0315 的 LNP 分别实现了 2 倍和 10 倍的 FVII 和 ADAMTS13 敲低。在高剂量（5 mg/kg）下，ALC-0315 LNP 会增加肝脏毒性标志物（ALT 和胆汁酸），而相同剂量的 MC3 LNP 则不会。这些结果表明，ALC-0315 LNP 在小鼠体内实现了 siRNA 介导的肝细胞和 HSC 靶蛋白的有效敲低，尽管在高剂量后可以观察到肝毒性标志物。这项研究提供了初步比较，可为开发具有最大功效和有限毒性的可电离阳离子 LNP 疗法提供信息。

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Comparison of DLin-MC3-DMA and ALC-0315 for siRNA Delivery to Hepatocytes and Hepatic Stellate Cells

Ionizable cationic lipids are essential for efficient in vivo delivery of RNA by lipid nanoparticles (LNPs). DLin-MC3-DMA (MC3), ALC-0315, and SM-102 are the only ionizable cationic lipids currently clinically approved for RNA therapies. ALC-0315 and SM-102 are structurally similar lipids used in SARS-CoV-2 mRNA vaccines, while MC3 is used in siRNA therapy to knock down transthyretin in hepatocytes. Hepatocytes and hepatic stellate cells (HSCs) are particularly attractive targets for RNA therapy because they synthesize many plasma proteins, including those that influence blood coagulation. While LNPs preferentially accumulate in the liver, evaluating the ability of different ionizable cationic lipids to deliver RNA cargo into distinct cell populations is important for designing RNA–LNP therapies with minimal hepatotoxicity. Here, we directly compared LNPs containing either ALC-0315 or MC3 to knock-down coagulation factor VII (FVII) in hepatocytes and ADAMTS13 in HSCs. At a dose of 1 mg/kg siRNA in mice, LNPs with ALC-0315 achieved a 2- and 10-fold greater knockdown of FVII and ADAMTS13, respectively, compared to LNPs with MC3. At a high dose (5 mg/kg), ALC-0315 LNPs increased markers of liver toxicity (ALT and bile acids), while the same dose of MC3 LNPs did not. These results demonstrate that ALC-0315 LNPs achieves potent siRNA-mediated knockdown of target proteins in hepatocytes and HSCs, in mice, though markers of liver toxicity can be observed after a high dose. This study provides an initial comparison that may inform the development of ionizable cationic LNP therapeutics with maximal efficacy and limited toxicity.

更新日期：2022-05-31

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