Local administration of a novel siRNA modality into the CNS extends survival and improves motor function in the SOD1G93A mouse model for ALS

IF 6.5 2区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Molecular Therapy. Nucleic Acids Pub Date : 2024-02-15 DOI:10.1016/j.omtn.2024.102147

Chunling Duan, Moorim Kang, Xiaojie Pan, Zubao Gan, Vera Huang, Guanlin Li, Robert F. Place, Long-Cheng Li

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Abstract

Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing in which short interfering RNAs (siRNAs) effectively degrade complementary transcripts. However, delivery to extrahepatic tissues like the central nervous system (CNS) has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 (hSOD1) in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enable activity in CNS tissues. Local delivery via intracerebroventricular (ICV) or intrathecal (IT) injection into SOD1 mice delayed disease progression and extended animal survival with superior efficacy compared to an ASO resembling Tofersen in sequence and chemistry. Treatment also prevented disease-related declines in motor function including improvements in animal mobility, muscle strength, and coordination. The ACO itself does not target any specific complementary nucleic acid sequence; rather, it imparts benefits conducive to bioavailability and delivery through its chemistry. The complete conjugate (, siRNA-ACO) represents a novel modality for delivery of duplex RNA (, siRNA) to the CNS that is currently being tested in the clinic for treatment of ALS.

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在 SOD1G93A ALS 小鼠模型中，向中枢神经系统局部施用新型 siRNA 可延长存活时间并改善运动功能

反义寡核苷酸（ASO）是治疗由突变型超氧化物歧化酶 1（SOD1）引起的肌萎缩性脊髓侧索硬化症（ALS）的第一种靶向基因敲除方法。RNA 干扰（RNAi）是另一种基因沉默机制，其中短干扰 RNA（siRNA）可有效降解互补转录本。然而，向中枢神经系统（CNS）等肝外组织的传递一直是 RNAi 临床开发的瓶颈。在本文中，我们发现了能有效敲除人 SOD1（hSOD1）的 siRNA 双链体，其中的药物化学成分和与辅助寡核苷酸（ACO）的连接使其在中枢神经系统组织中具有活性。通过脑室内（ICV）或鞘内（IT）注射给 SOD1 小鼠进行局部给药，可延缓疾病进展并延长动物存活期，其疗效优于在序列和化学性质上与 Tofersen 相似的 ASO。治疗还能防止与疾病相关的运动功能下降，包括改善动物的活动能力、肌肉力量和协调性。ACO 本身并不针对任何特定的互补核酸序列；相反，它通过其化学性质带来了有利于生物利用度和递送的益处。完整的共轭物（siRNA-ACO）代表了一种将双链 RNA（siRNA）输送到中枢神经系统的新模式，目前正在临床上进行测试，以治疗 ALS。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Molecular Therapy. Nucleic Acids MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

15.40

自引率

1.10%

发文量

336

审稿时长

20 weeks

期刊介绍： Molecular Therapy Nucleic Acids is an international, open-access journal that publishes high-quality research in nucleic-acid-based therapeutics to treat and correct genetic and acquired diseases. It is the official journal of the American Society of Gene & Cell Therapy and is built upon the success of Molecular Therapy. The journal focuses on gene- and oligonucleotide-based therapies and publishes peer-reviewed research, reviews, and commentaries. Its impact factor for 2022 is 8.8. The subject areas covered include the development of therapeutics based on nucleic acids and their derivatives, vector development for RNA-based therapeutics delivery, utilization of gene-modifying agents like Zn finger nucleases and triplex-forming oligonucleotides, pre-clinical target validation, safety and efficacy studies, and clinical trials.