HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Alterations in the hepatic transcriptional landscape after RNAi mediated ApoB silencing in cynomolgus monkeys.

Abstract
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.
AuthorsM Sabry Hamza, Chanchal Kumar, Ser Mien Chia, Vidhya Anandalakshmi, Nicole Boo, Walter Strapps, Michael Robinson, Michelle Caguyong, Steven Bartz, Marija Tadin-Strapps, Alain van Gool, Shian-Jiun Shih
JournalAtherosclerosis (Atherosclerosis) Vol. 242 Issue 2 Pg. 383-95 (Oct 2015) ISSN: 1879-1484 [Electronic] Ireland
PMID26275376 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2015 Elsevier Ireland Ltd. All rights reserved.
Chemical References
  • Apolipoproteins B
  • Lipids
  • RNA, Small Interfering
  • Cholesterol
Topics
  • Animals
  • Apolipoproteins B (genetics)
  • Biopsy
  • Cholesterol (metabolism)
  • Gene Expression Regulation
  • Genome
  • Genomics
  • Humans
  • Lipid Metabolism
  • Lipids (blood, chemistry)
  • Liver (metabolism, pathology)
  • Macaca fascicularis
  • Male
  • Nanoparticles (chemistry)
  • Oligonucleotide Array Sequence Analysis
  • Protein Biosynthesis
  • RNA Interference
  • RNA, Small Interfering (metabolism)
  • Real-Time Polymerase Chain Reaction

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: