bims-limsir Biomed News
on Lipophilic modified siRNAs
Issue of 2023–02–12
three papers selected by
Ivan V. Chernikov, Institute of Сhemical Biology and Fundamental Medicine of the SB RAS
  1. Metabolically Stable Anomeric Linkages Containing GalNAc-siRNA Conjugates: An Interplay among ASGPR, Glycosidase, and RISC Pathways.
  2. Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors: The Past and the Future.
  3. Genome Editing of Murine Liver Hepatocytes by AAV Vector-Mediated Expression of Cas9 In Vivo.
  1. J Med Chem. 2023 Feb 09.
    Metabolically Stable Anomeric Linkages Containing GalNAc-siRNA Conjugates: An Interplay among ASGPR, Glycosidase, and RISC Pathways.
    Pachamuthu Kandasamy, Shohei Mori, Shigeo Matsuda, Namrata Erande, Dhrubajyoti Datta, Jennifer L S Willoughby, Nate Taneja, Jonathan O'Shea, Anna Bisbe, Rajar M Manoharan, Kristina Yucius, Tuyen Nguyen, Ramesh Indrakanti, Swati Gupta, Jason A Gilbert, Tim Racie, Amy Chan, Ju Liu, Renta Hutabarat, Jayaprakash K Nair, Klaus Charisse, Martin A Maier, Kallanthottathil G Rajeev, Martin Egli, Muthiah Manoharan.
      Conjugation of synthetic triantennary N-acetyl-d-galactosamine (GalNAc) to small interfering RNA (siRNA) mediates binding to the asialoglycoprotein receptor (ASGPR) on the surface of hepatocytes, facilitating liver-specific uptake and siRNA-mediated gene silencing. The natural β-glycosidic bond of the GalNAc ligand is rapidly cleaved by glycosidases in vivo. Novel GalNAc ligands with S-, and C-glycosides with both α- and β-anomeric linkages, N-glycosides with β-anomeric linkage, and the O-glycoside with α-anomeric linkage were synthesized and conjugated to siRNA either on-column during siRNA synthesis or through a high-throughput, post-synthetic method. Unlike natural GalNAc, modified ligands were resistant to glycosidase activity. The siRNAs conjugated to newly designed ligands had similar affinities for ASGPR and similar silencing activity in mice as the parent GalNAc-siRNA conjugate. These data suggest that other factors, such as protein-nucleic acid interactions and loading of the antisense strand into the RNA-induced silencing complex (RISC), are more critical to the duration of action than the stereochemistry and stability of the anomeric linkage between the GalNAc moiety of the ligand conjugated to the sense strand of the siRNA.
    DOI:  https://doi.org/10.1021/acs.jmedchem.2c01337
  2. J Immunother Precis Oncol. 2023 Feb;6(1): 19-30
    Chimeric Antigen Receptor T-Cell Therapy for Solid Tumors: The Past and the Future.
    Samer A Srour, Serkan Akin.
      Chimeric antigen receptor (CAR) T-cell therapy is the new standard treatment for various indications in patients with advanced hematologic malignancies. Despite the several preclinical and early phase clinical trials, the overall clinical experience has been disappointing when applying this innovative therapy in solid tumors. The failure of CAR T-cell therapy and its limited antitumor activity in solid tumors have been attributed to several mechanisms, including tumor antigen heterogeneity, the hostile tumor microenvironment and poor trafficking of CAR T cells into tumor sites, and the unacceptable toxicities in some settings, among others. However, remarkable improvements have been made in understanding many of these failure mechanisms for which several emerging novel approaches are being applied to overcome these challenges. In this review, after a brief historic background for immunotherapy in solid tumors, we highlight the recent developments achieved in CAR T-cell designs, summarize completed clinical trials, and discuss current challenges facing CAR T-cell therapy and the suggested strategies to overcome these barriers.
    Keywords:  CAR T-cell; chimeric antigen receptor; immunotherapy; solid tumors
    DOI:  https://doi.org/10.36401/JIPO-22-7
  3. Methods Mol Biol. 2023 ;2637 195-211
    Genome Editing of Murine Liver Hepatocytes by AAV Vector-Mediated Expression of Cas9 In Vivo.
    Yuji Kashiwakura, Tsukasa Ohmori.
      Adeno-associated virus (AAV) vectors are attractive tools for gene transfer to the liver and are used as gene therapeutic drugs for inherited disorders. The intravenous injection of an AAV vector harboring the gene of interest driven by the hepatocyte-specific promoter could efficiently express the target gene in liver hepatocytes. The delivery of genome editing tools including Cas9 and gRNA, by the AAV vector, can efficiently disrupt the target gene expression in the liver in vivo by intravenous administration in mice. We can quickly obtain mice lacking specific gene expression in the liver only by administering the AAV vector. The method could be suitable for developing genome editing treatments for inherited disorders and basic research exploring the physiological role of the target gene produced from liver hepatocytes.
    Keywords:  Adeno-associated virus vector; CRISPR-Cas9; Hepatocyte-specific gene expression; Intravenous administration; Mouse model
    DOI:  https://doi.org/10.1007/978-1-0716-3016-7_15
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