Alterations in the hepatic transcriptional landscape after RNAi mediated ApoB silencing in cynomolgus monkeys.
The greater genomic conservation between humans and non-human primates (NHP) enables target validation studies for developing of therapeutic strategies for human diseases. Together with predicting activity and potential adverse clinical signs, the inclusion of NHP testing bequeaths to efficacy models for dose titration and pharmacodynamic effects. We have used lipid nanoparticle encapsulated siRNA to silence ApoB in the liver and assessed the phenotypic effects on serum lipids with various levels of hepatic ApoB mRNA knockdown in healthy lean cynomolgus monkeys. ApoB siRNA dosed animals demonstrated significant reductions of hepatic ApoB mRNA and serum APOB protein, with a substantial lowering of plasma lipid levels without obvious signs of toxicity. Microarray based assessment of ApoB siRNA mediated effects revealed a number of differentially expressed genes which mapped onto biological pathways and processes related to lipid and cholesterol metabolism. Furthermore, we identified potential targets and cellular effects that could be studied for therapeutic benchmarking of APOB mediated effects. The network of ApoB regulated genes should be of significance for the understanding and development of novel hypercholesterolemia therapies.
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore. Electronic address: sabry.hamza@merck.com.
M Sabry
MS
Hamza
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore.
Chanchal
C
Kumar
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore.
Ser Mien
SM
Chia
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore.
Vidhya
V
Anandalakshmi
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore.
Nicole
N
Boo
RNAi Therapeutics, Merck Research Labs, USA.
Walter
W
Strapps
RNAi Therapeutics, Merck Research Labs, USA.
Michael
M
Robinson
RNAi Therapeutics, Merck Research Labs, USA.
Michelle
M
Caguyong
RNAi Therapeutics, Merck Research Labs, USA.
Steven
S
Bartz
RNAi Therapeutics, Merck Research Labs, USA.
Marija
M
Tadin-Strapps
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore.
Alain
A
van Gool
Translational Medicine Research Centre, Merck Sharp and Dohme, Singapore. Electronic address: shian-jiun.shih@merck.com.
Shian-Jiun
SJ
Shih
D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics*; D001706:Biopsy; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation; D016678:Genome; D023281:Genomics; D006801:Humans; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood / Q000737:chemistry; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008252:Macaca fascicularis; D008297:Male; D053758:Nanoparticles / Q000737:chemistry; D020411:Oligonucleotide Array Sequence Analysis; D014176:Protein Biosynthesis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
D001055:Apolipoproteins B; D008055:Lipids; D034741:RNA, Small Interfering; D002784:Cholesterol
APOB; Cholesterol; Cynomolgus monkeys; NHP; Non-human primates; RNAi; siRNA