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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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. Lipophilic siRNA conjugates exert therapeutic activity in the mouse CNS.
AbstractList 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.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.
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.
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.
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.
Author Nair, Jayaprakash K.
Lentini, Scott
Woods, Lauren
Manoharan, Muthiah
Kasper, Anne
Zlatev, Ivan
Stricos, Matthew
Sutherland, Jessica E.
Milstein, Stuart
Wassarman, Kelly
Nguyen, Tuyen
Anglero-Rodriguez, Yesseinia I.
Allen, Jeffrey
Brown, Kirk M.
Castellanos-Rizaldos, Elena
Matsuda, Shigeo
Gilbert, Jason
Brown, Christopher
Johnson, Lei
Poreci, Urjana
Maier, Martin A.
Chickering, Tyler
Jiang, Yongfeng
Chigas, Samantha
Chong, Saeho
Peng, Haiyan
Dang, Lan T. H.
Fitzgerald, Kevin
Kelin, Alex
Charisse, Klaus
Racie, Timothy
Jadhav, Vasant
Rogers, Arlin B.
Guenther, Dale C.
Theile, Christopher S.
Jung, Michelle
Mobley, Melissa W.
Bombardier, Jessica
Agarwal, Saket
Kurz, Jeffrey
Li, Jing
LeBlanc, Sarah
Foster, Donald
Cha, Diana
Keating, Mark
Rollins, Jeff
Schlegel, Mark K.
Wu, Jing-Tao
Davis, Wendell
Janas, Maja M.
McDougall, Robin
Petrulis, John
Maganti, Rajanikanth
Castoreno, Adam
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/35654979$$D View this record in MEDLINE/PubMed
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Snippet Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional...
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SubjectTerms 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
Title Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates
URI https://link.springer.com/article/10.1038/s41587-022-01334-x
https://www.ncbi.nlm.nih.gov/pubmed/35654979
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Volume 40
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