Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy
Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease s...
| Үндсэн зохиолчид: | , , , , , , , , , , , , , , , |
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| Формат: | Journal article |
| Хэл сонгох: | English |
| Хэвлэсэн: |
Cell Press
2021
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| _version_ | 1826295298820931584 |
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| author | Cerro-Herreros, E González-Martínez, I Moreno, N Espinosa-Espinosa, J Fernández-Costa, JM Colom-Rodrigo, A Overby, SJ Seoane-Miraz, D Poyatos-García, J Vilchez, JJ López de Munain, A Varela, MA Wood, MJ Pérez-Alonso, M Llamusí, B Artero, R |
| author_facet | Cerro-Herreros, E González-Martínez, I Moreno, N Espinosa-Espinosa, J Fernández-Costa, JM Colom-Rodrigo, A Overby, SJ Seoane-Miraz, D Poyatos-García, J Vilchez, JJ López de Munain, A Varela, MA Wood, MJ Pérez-Alonso, M Llamusí, B Artero, R |
| author_sort | Cerro-Herreros, E |
| collection | OXFORD |
| description | Myotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40–60 pM 2 weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target.
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| first_indexed | 2024-03-07T03:58:53Z |
| format | Journal article |
| id | oxford-uuid:c3d0b98a-07cd-41e3-9c0c-d5cbc06b6798 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:58:53Z |
| publishDate | 2021 |
| publisher | Cell Press |
| record_format | dspace |
| spelling | oxford-uuid:c3d0b98a-07cd-41e3-9c0c-d5cbc06b67982022-03-27T06:19:24ZPreclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophyJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c3d0b98a-07cd-41e3-9c0c-d5cbc06b6798EnglishSymplectic ElementsCell Press2021Cerro-Herreros, EGonzález-Martínez, IMoreno, NEspinosa-Espinosa, JFernández-Costa, JMColom-Rodrigo, AOverby, SJSeoane-Miraz, DPoyatos-García, JVilchez, JJLópez de Munain, AVarela, MAWood, MJPérez-Alonso, MLlamusí, BArtero, RMyotonic dystrophy type 1 (DM1) is a rare neuromuscular disease caused by expansion of unstable CTG repeats in a non-coding region of the DMPK gene. CUG expansions in mutant DMPK transcripts sequester MBNL1 proteins in ribonuclear foci. Depletion of this protein is a primary contributor to disease symptoms such as muscle weakness and atrophy and myotonia, yet upregulation of endogenous MBNL1 levels may compensate for this sequestration. Having previously demonstrated that antisense oligonucleotides against miR-218 boost MBNL1 expression and rescue phenotypes in disease models, here we provide preclinical characterization of an antagomiR-218 molecule using the HSALR mouse model and patient-derived myotubes. In HSALR, antagomiR-218 reached 40–60 pM 2 weeks after injection, rescued molecular and functional phenotypes in a dose- and time-dependent manner, and showed a good toxicity profile after a single subcutaneous administration. In muscle tissue, antagomiR rescued the normal subcellular distribution of Mbnl1 and did not alter the proportion of myonuclei containing CUG foci. In patient-derived cells, antagomiR-218 improved defective fusion and differentiation and rescued up to 34% of the gene expression alterations found in the transcriptome of patient cells. Importantly, miR-218 was found to be upregulated in DM1 muscle biopsies, pinpointing this microRNA (miRNA) as a relevant therapeutic target. |
| spellingShingle | Cerro-Herreros, E González-Martínez, I Moreno, N Espinosa-Espinosa, J Fernández-Costa, JM Colom-Rodrigo, A Overby, SJ Seoane-Miraz, D Poyatos-García, J Vilchez, JJ López de Munain, A Varela, MA Wood, MJ Pérez-Alonso, M Llamusí, B Artero, R Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy |
| title | Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy |
| title_full | Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy |
| title_fullStr | Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy |
| title_full_unstemmed | Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy |
| title_short | Preclinical characterization of antagomiR-218 as a potential treatment for myotonic dystrophy |
| title_sort | preclinical characterization of antagomir 218 as a potential treatment for myotonic dystrophy |
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