Oligonucleotide therapeutics, including antisense oligonucleotides (ASOs) and duplex RNAs like siRNA, saRNA, and miRNA, hold immense potential for treating genetic and acquired diseases by modulating gene expression in a target-specific manner. However, effective delivery to extrahepatic tissues, particularly the central nervous system (CNS), remains a significant challenge. While GalNAc conjugation has enabled liver-specific delivery, leading to several approved siRNA drugs for hepatic targets, CNS delivery lags. ASOs, on the other hand, can self-deliver to the CNS when administered locally, as seen with nusinersen and tofersen. To address this disparity, we've developed the Smart Chemistry Aided Delivery (SCAD) platform which enables duplex RNA delivery by conjugating it to an accessory oligonucleotide (ACO), which acts as an aptamer to mediate protein binding and facilitate cellular uptake. Through extensive screening, we identified an optimal SCAD architecture that demonstrates enhanced cell-free protein binding and in vitro activity. In rodent models, local administration of SCAD-siRNA conjugates resulted in broad biodistribution throughout the CNS and sustained mRNA knockdown for over five months, with a favorable safety profile. The SCAD platform also exhibited efficient delivery to other tissues, including the eye, the lung and the joint. These features support its potential for broader clinical applications, as evidenced by an ongoing trial targeting amyotrophic lateral sclerosis (ALS) associated with mutations in the SOD1 gene. The modular design of SCAD allows it to easily adapt to any duplex RNA, making it a powerful tool for advancing oligonucleotide therapeutics.

中文翻译：

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SCAD 递送平台：一种高效的 CNS 和肝外寡核苷酸治疗的新方法


寡核苷酸疗法，包括反义寡核苷酸 （ASO） 和双链 RNA，如 siRNA、saRNA 和 miRNA，通过以靶标特异性方式调节基因表达，在治疗遗传和获得性疾病方面具有巨大潜力。然而，有效递送至肝外组织，尤其是中枢神经系统 （CNS） 仍然是一个重大挑战。虽然 GalNAc 偶联实现了肝脏特异性递送，导致了几种已获批用于肝脏靶标的 siRNA 药物，但 CNS 递送滞后。另一方面，ASO 在局部给药时可以自行输送到 CNS，如 nusinersen 和 tofersen。为了解决这一差异，我们开发了智能化学辅助递送 （SCAD） 平台，该平台通过将 RNA 与辅助寡核苷酸 （ACO） 偶联来实现双链 RNA 递送，辅助寡核苷酸 （ACO） 充当适配体，介导蛋白质结合并促进细胞摄取。通过广泛的筛选，我们确定了一种最佳的 SCAD 结构，该结构表现出增强的游离蛋白结合和体外活性。在啮齿动物模型中，SCAD-siRNA 偶联物的局部给药导致整个 CNS 中的广泛生物分布，并且 mRNA 敲低持续超过 5 个月，具有良好的安全性。SCAD 平台还表现出对其他组织（包括眼睛、肺和关节）的有效递送。这些特征支持了其更广泛的临床应用潜力，正在进行的针对与 SOD1 基因突变相关的肌萎缩侧索硬化症 （ALS） 的试验证明了这一点。SCAD 的模块化设计使其能够轻松适应任何双链 RNA，使其成为推进寡核苷酸治疗的强大工具。