bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2023–01–22
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
  2. Effective carrier-free gene-silencing activity of sphingosine-modified siRNAs.
  1. RNA. 2023 Jan 20. pii: rna.079507.122. [Epub ahead of print]
    Endosomal escape of RNA therapeutics: How do we solve this rate-limiting problem?
    Steven F Dowdy.
      With over 15 FDA approved drugs on the market and numerous ongoing clinical trials, RNA therapeutics, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs), have shown great potential to treat human disease. Their mechanism of action is based entirely on the sequence of validated disease-causing genes without the prerequisite knowledge of protein structure, activity or cellular location. In contrast to small molecule therapeutics that passively diffuse across the cell membrane's lipid bilayer, RNA therapeutics are too large, too charged and/or too hydrophilic to passively diffuse across the cellular membrane and instead are taken up into cells by endocytosis. However, endosomes are also composed of a lipid bilayer barrier that results in endosomal capture and retention of 99% of RNA therapeutics with 1% or less entering the cytoplasm. Although this very low level of endosomal escape has proven sufficient for liver and some CNS disorders, it is insufficient for the vast majority of extra-hepatic diseases. Unfortunately, there are currently no acceptable solutions to the endosomal escape problem. Consequently, before RNA therapeutics can be used to treat widespread human disease, the rate-limiting delivery problem of endosomal escape must be solved in a non-toxic manner.
    Keywords:  ASOs; RNA therapeutics; delivery; endosomal escape; siRNAs
    DOI:  https://doi.org/10.1261/rna.079507.122
  2. Org Biomol Chem. 2023 Jan 16.
    Effective carrier-free gene-silencing activity of sphingosine-modified siRNAs.
    Charlene Fernandez, Ifrodet Giorgees, Eva Goss, Jean-Paul Desaulniers.
      RNA interference (RNAi) is a natural cellular process that silences the expression of target genes in a sequence-specific way by mediating targeted mRNA degradation. One of the main challenges in RNAi research is developing an effective career-free delivery system and targeting cells in the central nervous system (CNS). Recently, lipid-conjugated systems involving fatty acids have shown promising potential as safe and effective delivery systems of oligonucleotides to CNS cells due to their hydrophobic tails and interactions with the cell's hydrophobic membrane. Therefore, in this study, we are interested in creating career-free siRNA therapeutics for potential applications in drug delivery to the CNS. Here we explore different synthetic pathways of conjugating sphingolipids containing long-carbon chains to siRNA and assess their effectiveness as career-free delivery systems. In this project, a library of sphingosine-modified siRNAs was created, and their gene-silencing effect was evaluated in both the presence and absence of a transfection carrier. siRNAs modified with one or two sphingosine moieties resulted in dose-dependent gene knockdown while demonstrating promising results for their use as carrier-free agents. The IC50 values of single-modified siRNAs ranged from 49.9 nM to 670.7 nM, whereas double-modified siRNAs had IC50 values in the range of 49.9 nM to 66.4 nM. In conclusion, sphingosine-modified siRNAs show promising results in advancing carrier-free siRNA therapeutics.
    DOI:  https://doi.org/10.1039/d2ob02099h
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