Biology subjects

Li, L.-C.

Publications and source records attributed to Li, L.-C..

3 recordsLinked to original sources

bioRxiv2024

SCAD Delivery Platform: A Novel Approach for Efficient CNS and Extrahepatic Oligonucleotide Therapeutics

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, weve 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.

neuroscience↗

bioRxiv2023

RAG-17: A Novel siRNA Conjugate Demonstrating Efficacy in Late-Stage Treatment of SOD1G93A ALS mice

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by rapid progression and high mortality. With genetic mutations, particularly in the SOD1 gene, playing a significant role in ALS pathogenesis, targeted therapies have become a primary focus. This study introduces RD-12500 (RAG-17), a novel siRNA-ACO (Accessory Oligonucleotide) conjugate designed to address the challenges of delivering duplex RNAs to the central nervous system (CNS). RD-12500 exhibits remarkable in vitro stability and target specificity with minimal immunostimulation. In vivo studies demonstrate its extensive CNS biodistribution, sustained accumulation post-intrathecal administration, and a robust dose-exposure-activity correlation. Notably, RD-12500 significantly reduces cerebrospinal fluid (CSF) SOD1 protein levels, indicating potent SOD1 mRNA and protein knockdown in cynomolgus monkeys. Most notably, our study breaks new ground by demonstrating the effectiveness of RD-12500 in late-stage treatment scenarios. In SOD1G93A ALS mice, post-onset administration of RD-12500 significantly delayed disease progression, improved motor function, and extended survival, marking a significant advancement over other treatments which are typically initiated pre-symptomatically in the same model mice. These findings suggest RD-12500s potential to provide therapeutic benefits not only to pre-symptomatic but also to post-symptomatic and late-stage SOD1-ALS patients.

pharmacology and toxicology↗

bioRxiv2023

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

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 SOD1G93A 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.

cell biology↗