| 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
|
| PII |
PGENETICS-D-18-00739
|
| 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
|
| Resource |
| Mice |
RBRC02796 |
