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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Published in:Nature biotechnology Vol. 40; no. 10; pp. 1500 - 1508
Main Authors: 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
Language:English
Published: New York Nature Publishing Group US 01.10.2022
Nature Publishing Group
Subjects:
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 Access:Get full text
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Summary: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.
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ISSN:1087-0156
1546-1696
1546-1696
DOI:10.1038/s41587-022-01334-x