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Towards next generation antisense oligonucleotides: mesylphosphoramidate modification improves therapeutic index and duration of effect of gapmer antisense oligonucleotides.
Anderson, Brooke A; Freestone, Graeme C; Low, Audrey; De-Hoyos, Cheryl L; Iii, William J Drury; Østergaard, Michael E; Migawa, Michael T; Fazio, Michael; Wan, W Brad; Berdeja, Andres; Scandalis, Eli; Burel, Sebastien A; Vickers, Timothy A; Crooke, Stanley T; Swayze, Eric E; Liang, Xuehai; Seth, Punit P.
Afiliación
  • Anderson BA; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Freestone GC; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Low A; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • De-Hoyos CL; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Iii WJD; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Østergaard ME; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Migawa MT; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Fazio M; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Wan WB; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Berdeja A; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Scandalis E; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Burel SA; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Vickers TA; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Crooke ST; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Swayze EE; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Liang X; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
  • Seth PP; Ionis Pharmaceuticals, 2855 Gazelle Court, Carlsbad, CA 92010, USA.
Nucleic Acids Res ; 49(16): 9026-9041, 2021 09 20.
Article en En | MEDLINE | ID: mdl-34417625
The PS modification enhances the nuclease stability and protein binding properties of gapmer antisense oligonucleotides (ASOs) and is one of very few modifications that support RNaseH1 activity. We evaluated the effect of introducing stereorandom and chiral mesyl-phosphoramidate (MsPA) linkages in the DNA gap and flanks of gapmer PS ASOs and characterized the effect of these linkages on RNA-binding, nuclease stability, protein binding, pro-inflammatory profile, antisense activity and toxicity in cells and in mice. We show that all PS linkages in a gapmer ASO can be replaced with MsPA without compromising chemical stability and RNA binding affinity but these designs reduced activity. However, replacing up to 5 PS in the gap with MsPA was well tolerated and replacing specific PS linkages at appropriate locations was able to greatly reduce both immune stimulation and cytotoxicity. The improved nuclease stability of MsPA over PS translated to significant improvement in the duration of ASO action in mice which was comparable to that of enhanced stabilized siRNA designs. Our work highlights the combination of PS and MsPA linkages as a next generation chemical platform for identifying ASO drugs with improved potency and therapeutic index, reduced pro-inflammatory effects and extended duration of effect.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligonucleótidos Antisentido / Índice Terapéutico de los Medicamentos Límite: Animals / Humans / Male Idioma: En Revista: Nucleic Acids Res Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligonucleótidos Antisentido / Índice Terapéutico de los Medicamentos Límite: Animals / Humans / Male Idioma: En Revista: Nucleic Acids Res Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido