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RNAi-mediated gene silencing in non-human primates

The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of tar... Full description

Journal Title: Nature 2006, Vol.441 (7089), p.111-114
Main Author: Wheat, Amanda J
Other Authors: Vornlocher, Hans-Peter , Röhl, Ingo , Lam, Kieu , McClintock, Kevin , Koteliansky, Victor , Yaworski, Ed , Jeffs, Lloyd B , MacLachlan, Ian , Soutschek, Jürgen , Toudjarska, Ivanka , Palmer, Lorne R , Heyes, James A , Zedalis, William , Akinc, Akin , Lee, Amy C. H , Bumcrot, David , Manoharan, Muthiah , Judge, Adam D , Racie, Timothy , Shanmugam, Sumi , Sood, Vandana , Seiffert, Stephan , Bramlage, Birgit , Fedoruk, Matthew N , Harborth, Jens , Zimmermann, Tracy S , John, Matthias , Nechev, Lubomir V
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: London: Nature Publishing
ID: ISSN: 0028-0836
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title: RNAi-mediated gene silencing in non-human primates
format: Article
creator:
  • Wheat, Amanda J
  • Vornlocher, Hans-Peter
  • Röhl, Ingo
  • Lam, Kieu
  • McClintock, Kevin
  • Koteliansky, Victor
  • Yaworski, Ed
  • Jeffs, Lloyd B
  • MacLachlan, Ian
  • Soutschek, Jürgen
  • Toudjarska, Ivanka
  • Palmer, Lorne R
  • Heyes, James A
  • Zedalis, William
  • Akinc, Akin
  • Lee, Amy C. H
  • Bumcrot, David
  • Manoharan, Muthiah
  • Judge, Adam D
  • Racie, Timothy
  • Shanmugam, Sumi
  • Sood, Vandana
  • Seiffert, Stephan
  • Bramlage, Birgit
  • Fedoruk, Matthew N
  • Harborth, Jens
  • Zimmermann, Tracy S
  • John, Matthias
  • Nechev, Lubomir V
subjects:
  • Animals
  • Apolipoproteins B - deficiency
  • Apolipoproteins B - genetics
  • Apolipoproteins B - metabolism
  • Biological and medical sciences
  • Biotechnology
  • Cynomolgus
  • Fundamental and applied biological sciences. Psychology
  • Health. Pharmaceutical industry
  • Industrial applications and implications. Economical aspects
  • Other active biomolecules
  • Phenotype
  • Primates
  • Primates - genetics
  • Production of active biomolecules
  • RNA Interference - drug effects
  • RNA, Messenger - genetics
  • RNA, Messenger - metabolism
  • RNA, Small Interfering - administration & dosage
  • RNA, Small Interfering - genetics
  • RNA, Small Interfering - metabolism
  • RNA, Small Interfering - pharmacology
ispartof: Nature, 2006, Vol.441 (7089), p.111-114
description: The opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg-1. A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
language: eng
source:
identifier: ISSN: 0028-0836
fulltext: no_fulltext
issn:
  • 0028-0836
  • 1476-4687
  • 1476-4679
url: Link


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titleRNAi-mediated gene silencing in non-human primates
creatorWheat, Amanda J ; Vornlocher, Hans-Peter ; Röhl, Ingo ; Lam, Kieu ; McClintock, Kevin ; Koteliansky, Victor ; Yaworski, Ed ; Jeffs, Lloyd B ; MacLachlan, Ian ; Soutschek, Jürgen ; Toudjarska, Ivanka ; Palmer, Lorne R ; Heyes, James A ; Zedalis, William ; Akinc, Akin ; Lee, Amy C. H ; Bumcrot, David ; Manoharan, Muthiah ; Judge, Adam D ; Racie, Timothy ; Shanmugam, Sumi ; Sood, Vandana ; Seiffert, Stephan ; Bramlage, Birgit ; Fedoruk, Matthew N ; Harborth, Jens ; Zimmermann, Tracy S ; John, Matthias ; Nechev, Lubomir V
creatorcontribWheat, Amanda J ; Vornlocher, Hans-Peter ; Röhl, Ingo ; Lam, Kieu ; McClintock, Kevin ; Koteliansky, Victor ; Yaworski, Ed ; Jeffs, Lloyd B ; MacLachlan, Ian ; Soutschek, Jürgen ; Toudjarska, Ivanka ; Palmer, Lorne R ; Heyes, James A ; Zedalis, William ; Akinc, Akin ; Lee, Amy C. H ; Bumcrot, David ; Manoharan, Muthiah ; Judge, Adam D ; Racie, Timothy ; Shanmugam, Sumi ; Sood, Vandana ; Seiffert, Stephan ; Bramlage, Birgit ; Fedoruk, Matthew N ; Harborth, Jens ; Zimmermann, Tracy S ; John, Matthias ; Nechev, Lubomir V
descriptionThe opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg-1. A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
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subjectAnimals ; Apolipoproteins B - deficiency ; Apolipoproteins B - genetics ; Apolipoproteins B - metabolism ; Biological and medical sciences ; Biotechnology ; Cynomolgus ; Fundamental and applied biological sciences. Psychology ; Health. Pharmaceutical industry ; Industrial applications and implications. Economical aspects ; Other active biomolecules ; Phenotype ; Primates ; Primates - genetics ; Production of active biomolecules ; RNA Interference - drug effects ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; RNA, Small Interfering - administration & dosage ; RNA, Small Interfering - genetics ; RNA, Small Interfering - metabolism ; RNA, Small Interfering - pharmacology
ispartofNature, 2006, Vol.441 (7089), p.111-114
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1Vornlocher, Hans-Peter
2Röhl, Ingo
3Lam, Kieu
4McClintock, Kevin
5Koteliansky, Victor
6Yaworski, Ed
7Jeffs, Lloyd B
8MacLachlan, Ian
9Soutschek, Jürgen
10Toudjarska, Ivanka
11Palmer, Lorne R
12Heyes, James A
13Zedalis, William
14Akinc, Akin
15Lee, Amy C. H
16Bumcrot, David
17Manoharan, Muthiah
18Judge, Adam D
19Racie, Timothy
20Shanmugam, Sumi
21Sood, Vandana
22Seiffert, Stephan
23Bramlage, Birgit
24Fedoruk, Matthew N
25Harborth, Jens
26Zimmermann, Tracy S
27John, Matthias
28Nechev, Lubomir V
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descriptionThe opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg-1. A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
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16RNA, Messenger - genetics
17RNA, Messenger - metabolism
18RNA, Small Interfering - administration & dosage
19RNA, Small Interfering - genetics
20RNA, Small Interfering - metabolism
21RNA, Small Interfering - pharmacology
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titleRNAi-mediated gene silencing in non-human primates
authorWheat, Amanda J ; Vornlocher, Hans-Peter ; Röhl, Ingo ; Lam, Kieu ; McClintock, Kevin ; Koteliansky, Victor ; Yaworski, Ed ; Jeffs, Lloyd B ; MacLachlan, Ian ; Soutschek, Jürgen ; Toudjarska, Ivanka ; Palmer, Lorne R ; Heyes, James A ; Zedalis, William ; Akinc, Akin ; Lee, Amy C. H ; Bumcrot, David ; Manoharan, Muthiah ; Judge, Adam D ; Racie, Timothy ; Shanmugam, Sumi ; Sood, Vandana ; Seiffert, Stephan ; Bramlage, Birgit ; Fedoruk, Matthew N ; Harborth, Jens ; Zimmermann, Tracy S ; John, Matthias ; Nechev, Lubomir V
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1Apolipoproteins B - deficiency
2Apolipoproteins B - genetics
3Apolipoproteins B - metabolism
4Biological and medical sciences
5Biotechnology
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7Fundamental and applied biological sciences. Psychology
8Health. Pharmaceutical industry
9Industrial applications and implications. Economical aspects
10Other active biomolecules
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14Production of active biomolecules
15RNA Interference - drug effects
16RNA, Messenger - genetics
17RNA, Messenger - metabolism
18RNA, Small Interfering - administration & dosage
19RNA, Small Interfering - genetics
20RNA, Small Interfering - metabolism
21RNA, Small Interfering - pharmacology
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2Röhl, Ingo
3Lam, Kieu
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5Koteliansky, Victor
6Yaworski, Ed
7Jeffs, Lloyd B
8MacLachlan, Ian
9Soutschek, Jürgen
10Toudjarska, Ivanka
11Palmer, Lorne R
12Heyes, James A
13Zedalis, William
14Akinc, Akin
15Lee, Amy C. H
16Bumcrot, David
17Manoharan, Muthiah
18Judge, Adam D
19Racie, Timothy
20Shanmugam, Sumi
21Sood, Vandana
22Seiffert, Stephan
23Bramlage, Birgit
24Fedoruk, Matthew N
25Harborth, Jens
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14Akinc, Akin
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17Manoharan, Muthiah
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19Racie, Timothy
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abstractThe opportunity to harness the RNA interference (RNAi) pathway to silence disease-causing genes holds great promise for the development of therapeutics directed against targets that are otherwise not addressable with current medicines. Although there are numerous examples of in vivo silencing of target genes after local delivery of small interfering RNAs (siRNAs), there remain only a few reports of RNAi-mediated silencing in response to systemic delivery of siRNA, and there are no reports of systemic efficacy in non-rodent species. Here we show that siRNAs, when delivered systemically in a liposomal formulation, can silence the disease target apolipoprotein B (ApoB) in non-human primates. APOB-specific siRNAs were encapsulated in stable nucleic acid lipid particles (SNALP) and administered by intravenous injection to cynomolgus monkeys at doses of 1 or 2.5 mg kg-1. A single siRNA injection resulted in dose-dependent silencing of APOB messenger RNA expression in the liver 48 h after administration, with maximal silencing of >90%. This silencing effect occurred as a result of APOB mRNA cleavage at precisely the site predicted for the RNAi mechanism. Significant reductions in ApoB protein, serum cholesterol and low-density lipoprotein levels were observed as early as 24 h after treatment and lasted for 11 days at the highest siRNA dose, thus demonstrating an immediate, potent and lasting biological effect of siRNA treatment. Our findings show clinically relevant RNAi-mediated gene silencing in non-human primates, supporting RNAi therapeutics as a potential new class of drugs.
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