Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved..
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 for 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:299 |
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| Enthalten in: |
The Journal of biological chemistry - 299(2023), 12 vom: 05. Dez., Seite 105475 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Aggarwal, Geetika [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 02.01.2024 Date Revised 31.01.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.jbc.2023.105475 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
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| 100 | 1 | |a Aggarwal, Geetika |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation |
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| 500 | |a Date Revised 31.01.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 for 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a antisense oligonucleotides | |
| 650 | 4 | |a frontotemporal dementia | |
| 650 | 4 | |a haploinsufficiency | |
| 650 | 4 | |a microRNA | |
| 650 | 4 | |a progranulin | |
| 650 | 7 | |a 3' Untranslated Regions |2 NLM | |
| 650 | 7 | |a GRN protein, human |2 NLM | |
| 650 | 7 | |a Intercellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a Oligonucleotides, Antisense |2 NLM | |
| 650 | 7 | |a Progranulins |2 NLM | |
| 650 | 7 | |a RNA, Messenger |2 NLM | |
| 650 | 7 | |a MIRN29a microRNA, human |2 NLM | |
| 700 | 1 | |a Banerjee, Subhashis |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Spencer A |e verfasserin |4 aut | |
| 700 | 1 | |a Benchaar, Yousri |e verfasserin |4 aut | |
| 700 | 1 | |a Bélanger, Jasmine |e verfasserin |4 aut | |
| 700 | 1 | |a Sévigny, Myriam |e verfasserin |4 aut | |
| 700 | 1 | |a Smith, Denise M |e verfasserin |4 aut | |
| 700 | 1 | |a Niehoff, Michael L |e verfasserin |4 aut | |
| 700 | 1 | |a Pavlack, Monica |e verfasserin |4 aut | |
| 700 | 1 | |a de Vera, Ian Mitchelle S |e verfasserin |4 aut | |
| 700 | 1 | |a Petkau, Terri L |e verfasserin |4 aut | |
| 700 | 1 | |a Leavitt, Blair R |e verfasserin |4 aut | |
| 700 | 1 | |a Ling, Karen |e verfasserin |4 aut | |
| 700 | 1 | |a Jafar-Nejad, Paymaan |e verfasserin |4 aut | |
| 700 | 1 | |a Rigo, Frank |e verfasserin |4 aut | |
| 700 | 1 | |a Morley, John E |e verfasserin |4 aut | |
| 700 | 1 | |a Farr, Susan A |e verfasserin |4 aut | |
| 700 | 1 | |a Dutchak, Paul A |e verfasserin |4 aut | |
| 700 | 1 | |a Sephton, Chantelle F |e verfasserin |4 aut | |
| 700 | 1 | |a Nguyen, Andrew D |e verfasserin |4 aut | |
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