RNA干扰
基因敲除
基因沉默
小干扰RNA
寡核苷酸
SOD1
锁核酸
化学
癌症研究
药理学
细胞生物学
生物
核糖核酸
分子生物学
基因
突变体
生物化学
作者
Chunling Duan,Minho Kang,Xin Pan,Zubao Gan,Vera Huang,Guanlin Li,Robert F. Place,Long-Cheng Li
标识
DOI:10.1101/2023.02.27.530262
摘要
ABSTRACT Antisense oligonucleotides (ASOs) were the first modality to pioneer targeted gene knockdown in the treatment of ALS caused by mutant superoxide dismutase 1 (SOD1). RNA interference (RNAi) is another mechanism of gene silencing with historically superior potency in which short interfering RNAs (siRNAs) guide the RNA-induced silencing complex (RISC) to cleave complementary transcripts. However, delivery to extrahepatic tissues like the central nerve 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) enables durable and potent activity in CNS tissues. Local delivery via intracerebroventricular (ICV) or intrathecal (IT) injection into SOD1 G93A mice delayed disease progression and extended animal survival with superior efficacy compared to an ASO compound 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 ( i.e ., siRNA-ACO) represents a novel modality for delivery of RNAi to the CNS in which we aim to pursue ALS as an exemplary indication for clinical development.
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