Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection.

Autor: Hariharan VN; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Shin M; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Chang CW; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., O'Reilly D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Biscans A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Yamada K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Guo Z; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Somasundaran M; Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01655., Tang Q; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Monopoli K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Krishnamurthy PM; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Devi G; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., McHugh N; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Cooper DA; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Echeverria D; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Cruz J; Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA 01655., Chan IL; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Liu P; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Lim SY; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., McConnell J; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655., Singh SP; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Hildebrand S; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Sousa J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Davis SM; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Kennedy Z; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Ferguson C; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Godinho BMDC; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Thillier Y; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Caiazzi J; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Ly S; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Muhuri M; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655.; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655., Kelly K; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655., Humphries F; Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Cousineau A; Diabetes Center of Excellence and Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Parsi KM; Diabetes Center of Excellence and Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Li Q; MassBiologics, University of Massachusetts Chan Medical School, Worcester, MA 01655., Wang Y; MassBiologics, University of Massachusetts Chan Medical School, Worcester, MA 01655., Maehr R; Diabetes Center of Excellence and Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Gao G; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655.; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655.; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655., Korkin D; Department of Computer Science, and Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609., McDougall WM; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655., Finberg RW; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Fitzgerald KA; Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655.; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655., Wang JP; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655., Watts JK; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655.; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655., Khvorova A; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2023 Mar 14; Vol. 120 (11), pp. e2219523120. Date of Electronic Publication: 2023 Mar 09.
DOI: 10.1073/pnas.2219523120
Abstrakt: The continuous evolution of SARS-CoV-2 variants complicates efforts to combat the ongoing pandemic, underscoring the need for a dynamic platform for the rapid development of pan-viral variant therapeutics. Oligonucleotide therapeutics are enhancing the treatment of numerous diseases with unprecedented potency, duration of effect, and safety. Through the systematic screening of hundreds of oligonucleotide sequences, we identified fully chemically stabilized siRNAs and ASOs that target regions of the SARS-CoV-2 genome conserved in all variants of concern, including delta and omicron. We successively evaluated candidates in cellular reporter assays, followed by viral inhibition in cell culture, with eventual testing of leads for in vivo antiviral activity in the lung. Previous attempts to deliver therapeutic oligonucleotides to the lung have met with only modest success. Here, we report the development of a platform for identifying and generating potent, chemically modified multimeric siRNAs bioavailable in the lung after local intranasal and intratracheal delivery. The optimized divalent siRNAs showed robust antiviral activity in human cells and mouse models of SARS-CoV-2 infection and represent a new paradigm for antiviral therapeutic development for current and future pandemics.
Databáze: MEDLINE