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Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates.
Brown, Kirk M; Nair, Jayaprakash K; Janas, Maja M; Anglero-Rodriguez, Yesseinia I; Dang, Lan T H; Peng, Haiyan; Theile, Christopher S; Castellanos-Rizaldos, Elena; Brown, Christopher; Foster, Donald; Kurz, Jeffrey; Allen, Jeffrey; Maganti, Rajanikanth; Li, Jing; Matsuda, Shigeo; Stricos, Matthew; Chickering, Tyler; Jung, Michelle; Wassarman, Kelly; Rollins, Jeff; Woods, Lauren; Kelin, Alex; Guenther, Dale C; Mobley, Melissa W; Petrulis, John; McDougall, Robin; Racie, Timothy; Bombardier, Jessica; Cha, Diana; Agarwal, Saket; Johnson, Lei; Jiang, Yongfeng; Lentini, Scott; Gilbert, Jason; Nguyen, Tuyen; Chigas, Samantha; LeBlanc, Sarah; Poreci, Urjana; Kasper, Anne; Rogers, Arlin B; Chong, Saeho; Davis, Wendell; Sutherland, Jessica E; Castoreno, Adam; Milstein, Stuart; Schlegel, Mark K; Zlatev, Ivan; Charisse, Klaus; Keating, Mark; Manoharan, Muthiah.
Afiliación
  • Brown KM; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Nair JK; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Janas MM; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Anglero-Rodriguez YI; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Dang LTH; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Peng H; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Theile CS; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Castellanos-Rizaldos E; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Brown C; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Foster D; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Kurz J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Allen J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Maganti R; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Li J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Matsuda S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Stricos M; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Chickering T; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Jung M; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Wassarman K; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Rollins J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Woods L; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Kelin A; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Guenther DC; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Mobley MW; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Petrulis J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • McDougall R; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Racie T; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Bombardier J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Cha D; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Agarwal S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Johnson L; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Jiang Y; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Lentini S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Gilbert J; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Nguyen T; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Chigas S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • LeBlanc S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Poreci U; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Kasper A; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Rogers AB; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Chong S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Davis W; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Sutherland JE; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Castoreno A; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Milstein S; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Schlegel MK; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Zlatev I; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Charisse K; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Keating M; Alnylam Pharmaceuticals, Cambridge, MA, USA.
  • Manoharan M; Alnylam Pharmaceuticals, Cambridge, MA, USA.
Nat Biotechnol ; 40(10): 1500-1508, 2022 10.
Article en En | MEDLINE | ID: mdl-35654979
ABSTRACT
Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2'-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer's disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Precursor de Proteína beta-Amiloide / Tratamiento con ARN de Interferencia Límite: Animals Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Precursor de Proteína beta-Amiloide / Tratamiento con ARN de Interferencia Límite: Animals Idioma: En Revista: Nat Biotechnol Asunto de la revista: BIOTECNOLOGIA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos