Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates

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 sy...

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Veröffentlicht in:	Nature biotechnology Jg. 40; H. 10; S. 1500 - 1508
Hauptverfasser:	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, Fitzgerald, Kevin, Wu, Jing-Tao, Maier, Martin A., Jadhav, Vasant
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	New York Nature Publishing Group US 01.10.2022 Nature Publishing Group
Schlagworte:	631/154/152 692/308/2778 Agriculture Alzheimer's disease Amyloid precursor protein Bioinformatics Biomedical and Life Sciences Biomedical Engineering/Biotechnology Biomedicine Biotechnology Central nervous system Conjugates Conjugation Dosage Gene expression Gene silencing Hepatocytes Intranasal administration Life Sciences Lipophilic Lipophilicity Lungs Neurodegenerative diseases RNA-mediated interference siRNA
ISSN:	1087-0156, 1546-1696, 1546-1696
Online-Zugang:	Volltext
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Zusammenfassung:	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. Lipophilic siRNA conjugates exert therapeutic activity in the mouse CNS.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1087-0156 1546-1696 1546-1696
DOI:	10.1038/s41587-022-01334-x