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Series GSE184929 Query DataSets for GSE184929
Status Public on Jun 08, 2022
Title From Bench to Bedside and Back: Improving the Safety of GalNAc-siRNA Conjugates Using GNA-Destabilized Seed-Pairing
Organisms Homo sapiens; Rattus norvegicus
Experiment type Expression profiling by high throughput sequencing
Summary Preclinical mechanistic studies have pointed towards RNAi-mediated off-target effects as a major driver of hepatotoxicity for GalNAc-siRNA conjugates. Here we demonstrate that a single glycol nucleic acid (GNA) modification can substantially reduce siRNA seed-mediated binding to off-target transcripts while maintaining on-target activity. In siRNAs with established off-target effects leading to hepatotoxicity, these Enhanced Stabilization Chemistry plus (ESC+) designs exhibit a substantially improved therapeutic window in rat. We utilized this strategy to improve the safety of ALN-HBV, which exhibited dose-dependent, transient, and asymptomatic alanine aminotransferase elevations in healthy volunteers.
Overall design The increased specificity of GNA-containing GalNAc-siRNAs is demonstrated in vitro and in vivo using measures of differential expression derived from RNA-seq data.
Contributor(s) Schlegel MK, Janas MM, Jiang Y, Barry JD, Davis W, Agarwal S, Berman D, Brown CR, Castoreno A, LeBlanc S, Liebow A, Mayo T, Milstein S, Nguyen T, Shulga-Morskaya S, Solomon S, Szeto J, Woods LB, Yilmaz VO, Manoharan M, Charisse K, Sepp-Lorenzino L, Haslett P, Fitzgerald K, Jadhav V, Maier MA
Citation(s) 35736224
Submission date Sep 28, 2021
Last update date Jul 14, 2022
Contact name Joseph Barry
Organization name Alnylam Pharmaceuticals
Street address 675 West Kendall St
City Cambridge
State/province MA
ZIP/Postal code 02142
Country USA
Platforms (2)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
GPL20084 Illumina NextSeq 500 (Rattus norvegicus)
Samples (157)
GSM6209259 Liver Fig3-GO1_D6_10mkg_rep1
GSM6209260 Liver Fig3-GO1_D6_10mkg_rep2
GSM6209261 Liver Fig3-GO1_D6_10mkg_rep3
BioProject PRJNA767053
SRA SRP339148

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE184929_Fig3-GO1_groupD6_10mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD6_120mkg.vs.NaCl.DESeq2.txt.gz 1.2 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD6_30mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD6_3mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD6_60mkg.vs.NaCl.DESeq2.txt.gz 1.2 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD9_10mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD9_120mkg.vs.NaCl.DESeq2.txt.gz 1.2 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD9_30mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD9_3mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-GO1_groupD9_60mkg.vs.NaCl.DESeq2.txt.gz 1.2 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-1_groupD1_10mkg.vs.Mock.DESeq2.txt.gz 1.0 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-1_groupD1_3mkg.vs.Mock.DESeq2.txt.gz 1.0 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-1_groupD4_10mkg.vs.Mock.DESeq2.txt.gz 1.0 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-1_groupD4_3mkg.vs.Mock.DESeq2.txt.gz 1.0 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-2_groupD1_120mkg.vs.Mock.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-2_groupD1_30mkg.vs.Mock.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-2_groupD1_60mkg.vs.Mock.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-2_groupD4_120mkg.vs.Mock.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-2_groupD4_30mkg.vs.Mock.DESeq2.txt.gz 1.0 Mb (ftp)(http) TXT
GSE184929_Fig3-TTR-2_groupD4_60mkg.vs.Mock.DESeq2.txt.gz 1.0 Mb (ftp)(http) TXT
GSE184929_Fig4_groupD16_50nM.vs.mock.DESeq2.txt.gz 894.4 Kb (ftp)(http) TXT
GSE184929_Fig4_groupD1_50nM.vs.mock.DESeq2.txt.gz 917.4 Kb (ftp)(http) TXT
GSE184929_Fig4_groupD20_50nM.vs.mock.DESeq2.txt.gz 922.9 Kb (ftp)(http) TXT
GSE184929_Fig4_groupD4_50nM.vs.mock.DESeq2.txt.gz 875.3 Kb (ftp)(http) TXT
GSE184929_Fig4_groupD6_50nM.vs.mock.DESeq2.txt.gz 930.3 Kb (ftp)(http) TXT
GSE184929_Fig4_groupD9_50nM.vs.mock.DESeq2.txt.gz 903.3 Kb (ftp)(http) TXT
GSE184929_Fig5-HBV_groupALN-HBV02_10nM.vs.mock.DESeq2.txt.gz 1.4 Mb (ftp)(http) TXT
GSE184929_Fig5-HBV_groupALN-HBV_10nM.vs.mock.DESeq2.txt.gz 1.4 Mb (ftp)(http) TXT
GSE184929_FigS16-GO1_groupD12_30mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_FigS16-TTR_groupD11_30mkg.vs.NaCl.DESeq2.txt.gz 1.2 Mb (ftp)(http) TXT
GSE184929_FigS16-TTR_groupD1_30mkg.vs.NaCl.DESeq2.txt.gz 1.2 Mb (ftp)(http) TXT
GSE184929_FigS16-TTR_groupD4_30mkg.vs.NaCl.DESeq2.txt.gz 1.1 Mb (ftp)(http) TXT
GSE184929_RAW.tar 22.7 Mb (http)(custom) TAR (of TXT)
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Raw data are available in SRA
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