bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2024–01–14
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors.
  2. A programmable dual-targeting di-valent siRNA scaffold supports potent multi-gene modulation in the central nervous system.
  1. Mol Ther Nucleic Acids. 2024 Mar 12. 35(1): 102088
    Single intravitreal administration of a tetravalent siRNA exhibits robust and efficient gene silencing in mouse and pig photoreceptors.
    Shun-Yun Cheng, Jillian Caiazzi, Annabelle Biscans, Julia F Alterman, Dimas Echeverria, Nicholas McHugh, Matthew Hassler, Samson Jolly, Delaney Giguere, Joris Cipi, Anastasia Khvorova, Claudio Punzo.
      Inherited retinal dystrophies caused by dominant mutations in photoreceptor (PR) cell expressed genes are a major cause of irreversible vision loss. Oligonucleotide therapy has been of interest in diseases that conventional medicine cannot target. In the early days, small interfering RNAs (siRNAs) were explored in clinical trials for retinal disorders with limited success due to a lack of stability and efficient cellular delivery. Thus, an unmet need exists to identify siRNA chemistry that targets PR cell expressed genes. Here, we evaluated 12 different fully chemically modified siRNA configurations, where the valency and conjugate structure were systematically altered. The impact on retinal distribution following intravitreal delivery was examined. We found that the increase in valency (tetravalent siRNA) supports the best PR accumulation. A single intravitreal administration induces multimonths efficacy in rodent and porcine retinas while demonstrating a good safety profile. The data suggest that this configuration can treat retinal diseases caused by PR cell expressed genes with 1-2 intravitreal injections per year.
    Keywords:  IRD; MT: Oligonucleotides: Therapies and Applications; gene silencing; inherited retinal dystrophy; multivalency; photoreceptors; siRNA
    DOI:  https://doi.org/10.1016/j.omtn.2023.102088
  2. bioRxiv. 2023 Dec 19. pii: 2023.12.19.572404. [Epub ahead of print]
    A programmable dual-targeting di-valent siRNA scaffold supports potent multi-gene modulation in the central nervous system.
    Jillian Belgrad, Qi Tang, Sam Hildebrand, Ashley Summers, Ellen Sapp, Dimas Echeverria, Dan O'Reilly, Eric Luu, Brianna Bramato, Sarah Allen, David Cooper, Julia Alterman, Ken Yamada, Neil Aronin, Marian DiFiglia, Anastasia Khvorova.
      Di-valent short interfering RNA (siRNA) is a promising therapeutic modality that enables sequence-specific modulation of a single target gene in the central nervous system (CNS). To treat complex neurodegenerative disorders, where pathogenesis is driven by multiple genes or pathways, di-valent siRNA must be able to silence multiple target genes simultaneously. Here we present a framework for designing unimolecular "dual-targeting" di-valent siRNAs capable of co-silencing two genes in the CNS. We reconfigured di-valent siRNA - in which two identical, linked siRNAs are made concurrently - to create linear di-valent siRNA - where two siRNAs are made sequentially attached by a covalent linker. This linear configuration, synthesized using commercially available reagents, enables incorporation of two different siRNAs to silence two different targets. We demonstrate that this dual-targeting di-valent siRNA is fully functional in the CNS of mice, supporting at least two months of maximal target silencing. Dual-targeting di-valent siRNA is highly programmable, enabling simultaneous modulation of two different disease-relevant gene pairs (e.g., Huntington's disease: MSH3 and HTT ; Alzheimer's disease: APOE and JAK1 ) with similar potency to a mixture of single-targeting di-valent siRNAs against each gene. This work potentiates CNS modulation of virtually any pair of disease-related targets using a simple unimolecular siRNA.
    DOI:  https://doi.org/10.1101/2023.12.19.572404
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