Genomics

Dataset Information

0

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation


ABSTRACT: Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

ORGANISM(S): Homo sapiens

PROVIDER: GSE188498 | GEO | 2022/08/01

REPOSITORIES: GEO

Dataset's files

Source:
Action DRS
Other
Items per page:
1 - 1 of 1

Similar Datasets

2022-09-18 | PXD035889 | Pride
2020-08-02 | GSE143144 | GEO
2012-10-25 | E-GEOD-40378 | biostudies-arrayexpress
2011-08-31 | E-GEOD-31772 | biostudies-arrayexpress
2022-06-03 | GSE163122 | GEO
2012-10-25 | GSE40378 | GEO
2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress
2014-11-12 | GSE60902 | GEO
2011-09-01 | GSE31772 | GEO
2016-10-13 | PXD004087 | Pride