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A divalent siRNA chemical scaffold for potent and sustained modulation of gene expression throughout the central nervous system.
Alterman, Julia F; Godinho, Bruno M D C; Hassler, Matthew R; Ferguson, Chantal M; Echeverria, Dimas; Sapp, Ellen; Haraszti, Reka A; Coles, Andrew H; Conroy, Faith; Miller, Rachael; Roux, Loic; Yan, Paul; Knox, Emily G; Turanov, Anton A; King, Robert M; Gernoux, Gwladys; Mueller, Christian; Gray-Edwards, Heather L; Moser, Richard P; Bishop, Nina C; Jaber, Samer M; Gounis, Matthew J; Sena-Esteves, Miguel; Pai, Athma A; DiFiglia, Marian; Aronin, Neil; Khvorova, Anastasia.
Afiliación
  • Alterman JF; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Godinho BMDC; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Hassler MR; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Ferguson CM; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Echeverria D; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Sapp E; Department of Neurology, Massachusetts General Institute for Neurodegenerative Disease, Boston, MA, USA.
  • Haraszti RA; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Coles AH; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Conroy F; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Miller R; Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • Roux L; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Yan P; Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • Knox EG; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Turanov AA; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • King RM; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Gernoux G; RNA Therapeutics Institute, University of Massachusetts Medical School, Worcester, MA, USA.
  • Mueller C; Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, MA, USA.
  • Gray-Edwards HL; Department of Biomedical Engineering, Worcester Polytechnic Institute, Worcester, MA, USA.
  • Moser RP; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
  • Bishop NC; Horae Gene Therapy Center, University of Massachusetts Medical School, Worcester, MA, USA.
  • Jaber SM; Department of Pediatrics, University of Massachusetts Medical School, Worcester, MA, USA.
  • Gounis MJ; Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, MA, USA.
  • Sena-Esteves M; Department of Neurosurgery, University of Massachusetts Medical School, Worcester, MA, USA.
  • Pai AA; Department of Animal Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • DiFiglia M; Department of Animal Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
  • Aronin N; Department of Pathology, University of Massachusetts Medical School, Worcester, MA, USA.
  • Khvorova A; Department of Radiology, New England Center for Stroke Research, University of Massachusetts Medical School, Worcester, MA, USA.
Nat Biotechnol ; 37(8): 884-894, 2019 08.
Article en En | MEDLINE | ID: mdl-31375812
ABSTRACT
Sustained silencing of gene expression throughout the brain using small interfering RNAs (siRNAs) has not been achieved. Here we describe an siRNA architecture, divalent siRNA (di-siRNA), that supports potent, sustained gene silencing in the central nervous system (CNS) of mice and nonhuman primates following a single injection into the cerebrospinal fluid. Di-siRNAs are composed of two fully chemically modified, phosphorothioate-containing siRNAs connected by a linker. In mice, di-siRNAs induced the potent silencing of huntingtin, the causative gene in Huntington's disease, reducing messenger RNA and protein throughout the brain. Silencing persisted for at least 6 months, with the degree of gene silencing correlating to levels of guide strand tissue accumulation. In cynomolgus macaques, a bolus injection of di-siRNA showed substantial distribution and robust silencing throughout the brain and spinal cord without detectable toxicity and with minimal off-target effects. This siRNA design may enable RNA interference-based gene silencing in the CNS for the treatment of neurological disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Nervioso Central / Regulación de la Expresión Génica / ARN Interferente Pequeño / Proteína Huntingtina Límite: Animals Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sistema Nervioso Central / Regulación de la Expresión Génica / ARN Interferente Pequeño / Proteína Huntingtina Límite: Animals Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos