bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2024–03–10
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. From sequences to therapeutics: Using machine learning to predict chemically modified siRNA activity.
  2. Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1G93A ALS mouse model.
  1. Genomics. 2024 Mar 01. pii: S0888-7543(24)00036-3. [Epub ahead of print]116(2): 110815
    From sequences to therapeutics: Using machine learning to predict chemically modified siRNA activity.
    Dominic D Martinelli.
      Small interfering RNAs (siRNAs) exemplify the promise of genetic medicine in the discovery of novel therapeutic modalities. Their ability to selectively suppress gene expression makes them ideal candidates for the development of oligonucleotide pharmaceuticals. Recent advancements in machine learning (ML) have facilitated the design of unmodified siRNA and efficacy prediction. However, a model trained to predict the silencing activity of siRNAs with diverse chemical modification patterns is yet to be published despite the importance of such modifications in designing siRNAs with the potential to reach the level of clinical use. This study presents the first application of ML to efficiently classify chemically modified siRNAs on the basis of sequence and chemical modification patterns alone. Three algorithms were evaluated at three classification thresholds and compared according to sensitivity, specificity, consistency of feature weights with empirical knowledge, and performance using an external validation dataset. Finally, possible directions for future research were proposed.
    Keywords:  Artificial intelligence; Bioinformatics; Drug discovery; Gene therapy; RNA interference
    DOI:  https://doi.org/10.1016/j.ygeno.2024.110815
  2. Mol Ther Nucleic Acids. 2024 Mar 12. 35(1): 102147
    Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1G93A ALS mouse model.
    Chunling Duan, Moorim Kang, Xiaojie Pan, Zubao Gan, Vera Huang, Guanlin Li, Robert F Place, Long-Cheng Li.
      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 CNS has been a bottleneck in the clinical development of RNAi. Herein, we identify potent siRNA duplexes for the knockdown of human SOD1 in which medicinal chemistry and conjugation to an accessory oligonucleotide (ACO) enable activity in CNS tissues. Local delivery via intracerebroventricular or intrathecal injection into SOD1G93A mice delayed disease progression and extended animal survival with superior efficacy compared with 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 (i.e., siRNA-ACO) represents a novel modality for delivery of duplex RNA (e.g., siRNA) to the CNS that is currently being tested in the clinic for treatment of ALS.
    Keywords:  ALS; ASO; CNS; Lou Gehrig’s disease; MT: Oligonucleotides: Therapies and Applications; RNAi; SCAD; SOD1; SOD1G93A ALS mouse; amyotrophic lateral sclerosis; delivery; siRNA; siRNA-ACO
    DOI:  https://doi.org/10.1016/j.omtn.2024.102147
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