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

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Title: Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation.
Authors: Aggarwal, Geetika1,2,3, Banerjee, Subhashis1,2,3, Jones, Spencer A.1,2,3, Benchaar, Yousri4, Bélanger, Jasmine4, Sévigny, Myriam4, Smith, Denise M.1,2,3, Niehoff, Michael L.1,5, Pavlack, Monica2,3, de Vera, Ian Mitchelle S.2,3, Petkau, Terri L.6, Leavitt, Blair R.6,7,8, Ling, Karen9, Jafar-Nejad, Paymaan9, Rigo, Frank9, Morley, John E.1, Farr, Susan A.1,2,3,5, Dutchak, Paul A.4, Sephton, Chantelle F.4, Nguyen, Andrew D.1,2,3 andy.d.nguyen@health.slu.edu
Source: Journal of Biological Chemistry. Dec2023, Vol. 299 Issue 12, p1-11. 11p.
Subjects: Progranulin, Binding sites, Gene expression, Frontotemporal dementia, Messenger RNA, Oligonucleotides, Genetic 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 30 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 for miR-29b from binding to the GRN 30 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. [ABSTRACT FROM AUTHOR]
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Database: Engineering Source
Description
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 30 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 for miR-29b from binding to the GRN 30 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. [ABSTRACT FROM AUTHOR]
ISSN:00219258
DOI:10.1016/j.jbc.2023.105475