Your browser doesn't support javascript.
loading
Divalent siRNAs are bioavailable in the lung and efficiently block SARS-CoV-2 infection.
Hariharan, Vignesh N; Shin, Minwook; Chang, Ching-Wen; O'Reilly, Daniel; Biscans, Annabelle; Yamada, Ken; Guo, Zhiru; Somasundaran, Mohan; Tang, Qi; Monopoli, Kathryn; Krishnamurthy, Pranathi Meda; Devi, Gitali; McHugh, Nicholas; Cooper, David A; Echeverria, Dimas; Cruz, John; Chan, Io Long; Liu, Ping; Lim, Sun-Young; McConnell, Jill; Singh, Satya Prakash; Hildebrand, Samuel; Sousa, Jacquelyn; Davis, Sarah M; Kennedy, Zachary; Ferguson, Chantal; Godinho, Bruno M D C; Thillier, Yann; Caiazzi, Jillian; Ly, Socheata; Muhuri, Manish; Kelly, Karen; Humphries, Fiachra; Cousineau, Alyssa; Parsi, Krishna Mohan; Li, Qi; Wang, Yang; Maehr, René; Gao, Guangping; Korkin, Dmitry; McDougall, William M; Finberg, Robert W; Fitzgerald, Katherine A; Wang, Jennifer P; Watts, Jonathan K; Khvorova, Anastasia.
Afiliación
  • 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.
  • Kelly K; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Humphries F; RNA Therapeutics Institute, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Cousineau A; Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of 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; Diabetes Center of Excellence and Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Wang Y; MassBiologics, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Maehr R; MassBiologics, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Gao G; Diabetes Center of Excellence and Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Korkin D; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • McDougall WM; Horae Gene Therapy Center, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Finberg RW; Li Weibo Institute for Rare Diseases Research, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Fitzgerald KA; Department of Computer Science, and Bioinformatics and Computational Biology Program, Worcester Polytechnic Institute, Worcester, MA 01609.
  • Wang JP; Department of Microbiology and Physiological Systems, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Watts JK; Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655.
  • Khvorova A; Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01655.
Proc Natl Acad Sci U S A ; 120(11): e2219523120, 2023 03 14.
Article en En | MEDLINE | ID: mdl-36893269
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.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: COVID-19 Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: COVID-19 Límite: Animals / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2023 Tipo del documento: Article Pais de publicación: Estados Unidos