RRC ID 54339
Author Pirie E, Ray S, Pan C, Fu W, Powers AF, Polikoff D, Miller CM, Kudrna KM, Harris EN, Lusis AJ, Crooke RM, Lee RG.
Title Mouse genome-wide association studies and systems genetics uncover the genetic architecture associated with hepatic pharmacokinetic and pharmacodynamic properties of a constrained ethyl antisense oligonucleotide targeting Malat1.
Journal PLoS Genet
Abstract Antisense oligonucleotides (ASOs) have demonstrated variation of efficacy in patient populations. This has prompted our investigation into the contribution of genetic architecture to ASO pharmacokinetics (PK) and pharmacodynamics (PD). Genome wide association (GWA) and transcriptomic analysis in a hybrid mouse diversity panel (HMDP) were used to identify and validate novel genes involved in the uptake and efficacy of a single dose of a Malat1 constrained ethyl (cEt) modified ASO. The GWA of the HMDP identified two significant associations on chromosomes 4 and 10 with hepatic Malat1 ASO concentrations. Stabilin 2 (Stab2) and vesicle associated membrane protein 3 (Vamp3) were identified by cis-eQTL analysis. HMDP strains with lower Stab2 expression and Stab2 KO mice displayed significantly lower PK than strains with higher Stab2 expression and the wild type (WT) animals respectively, confirming the role of Stab2 in regulating hepatic Malat1 ASO uptake. GWA examining ASO efficacy uncovered three loci associated with Malat1 potency: Small Subunit Processome Component (Utp11l) on chromosome 4, Rho associated coiled-coil containing protein kinase 2 (Rock2) and Aci-reductone dioxygenase (Adi1) on chromosome 12. Our results demonstrate the utility of mouse GWAS using the HMDP in detecting genes capable of impacting the uptake of ASOs, and identifies genes critical for the activity of ASOs in vivo.
Volume 14(10)
Pages e1007732
Published 2018-10-1
DOI 10.1371/journal.pgen.1007732
PMID 30372444
PMC PMC6224167
MeSH Animals Cell Adhesion Molecules, Neuronal / genetics Cell Adhesion Molecules, Neuronal / metabolism Gene Expression Profiling / methods Genetic Variation Genome-Wide Association Study Liver / metabolism Mice Mice, Knockout Oligonucleotides, Antisense / genetics Oligonucleotides, Antisense / pharmacokinetics* RNA, Long Noncoding / genetics* RNA, Long Noncoding / physiology* RNA, Messenger / metabolism Vesicle-Associated Membrane Protein 3 / genetics Vesicle-Associated Membrane Protein 3 / metabolism
IF 5.175
Times Cited 4
Mice RBRC02796