bims-limsir 2023-11-12 papers

on Lipophilic modified siRNAs

Issue of 2023–11–12
two papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.
Cholesterol-Conjugated Supramolecular Multimeric siRNAs: Effect of siRNA Length on Accumulation and Silencing In Vitro and In Vivo.

Nat Commun. 2023 Nov 04. 14(1): 7099

Rational design of a JAK1-selective siRNA inhibitor for the modulation of autoimmunity in the skin.

Qi Tang, Hassan H Fakih, Mohammad Zain Ui Abideen, Samuel R Hildebrand, Khashayar Afshari, Katherine Y Gross, Jacquelyn Sousa, Allison S Maebius, Christina Bartholdy, Pia Pernille Søgaard, Malene Jackerott, Vignesh Hariharan, Ashley Summers, Xueli Fan, Ken Okamura, Kathryn R Monopoli, David A Cooper, Dimas Echeverria, Brianna Bramato, Nicholas McHugh, Raymond C Furgal, Karen Dresser, Sarah J Winter, Annabelle Biscans, Jane Chuprin, Nazgol-Sadat Haddadi, Shany Sherman, Ümmügülsüm Yıldız-Altay, Mehdi Rashighi, Jillian M Richmond, Claire Bouix-Peter, Carine Blanchard, Adam Clauss, Julia F Alterman, Anastasia Khvorova, John E Harris.

Inhibition of Janus kinase (JAK) family enzymes is a popular strategy for treating inflammatory and autoimmune skin diseases. In the clinic, small molecule JAK inhibitors show distinct efficacy and safety profiles, likely reflecting variable selectivity for JAK subtypes. Absolute JAK subtype selectivity has not yet been achieved. Here, we rationally design small interfering RNAs (siRNAs) that offer sequence-specific gene silencing of JAK1, narrowing the spectrum of action on JAK-dependent cytokine signaling to maintain efficacy and improve safety. Our fully chemically modified siRNA supports efficient silencing of JAK1 expression in human skin explant and modulation of JAK1-dependent inflammatory signaling. A single injection into mouse skin enables five weeks of duration of effect. In a mouse model of vitiligo, local administration of the JAK1 siRNA significantly reduces skin infiltration of autoreactive CD8+ T cells and prevents epidermal depigmentation. This work establishes a path toward siRNA treatments as a new class of therapeutic modality for inflammatory and autoimmune skin diseases.

DOI: https://doi.org/10.1038/s41467-023-42714-4
Nucleic Acid Ther. 2023 Nov 09.

Cholesterol-Conjugated Supramolecular Multimeric siRNAs: Effect of siRNA Length on Accumulation and Silencing In Vitro and In Vivo.

Ivan V Chernikov, Ul'yana A Ponomareva, Mariya I Meschaninova, Irina K Bachkova, Anna A Teterina, Daniil V Gladkikh, Innokenty A Savin, Valentin V Vlassov, Marina A Zenkova, Elena L Chernolovskaya.

  Conjugation of small interfering RNA (siRNA) with lipophilic molecules is one of the most promising approaches for delivering siRNA in vivo. The rate of molecular weight-dependent siRNA renal clearance is critical for the efficiency of this process. In this study, we prepared cholesterol-containing supramolecular complexes containing from three to eight antisense strands and examined their accumulation and silencing activity in vitro and in vivo. We have shown for the first time that such complexes with 2'F, 2'OMe, and LNA modifications exhibit interfering activity both in carrier-mediated and carrier-free modes. Silencing data from a xenograft tumor model show that 4 days after intravenous injection of cholesterol-containing monomers and supramolecular trimers, the levels of MDR1 mRNA in the tumor decreased by 85% and 68%, respectively. The in vivo accumulation data demonstrated that the formation of supramolecular structures with three or four antisense strands enhanced their accumulation in the liver. After addition of two PS modifications at the ends of antisense strands, 47% and 67% reductions of Ttr mRNA levels in the liver tissue were detected 7 days after administration of monomers and supramolecular trimers, respectively. Thus, we have obtained a new type of RNAi inducer that is convenient for synthesis and provides opportunities for modifications.

Keywords:  MDR1; TTR; biodistribution; chemically modified siRNA; cholesterol conjugate; supramolecular siRNA

DOI:  https://doi.org/10.1089/nat.2023.0051