Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansions in DM1 protein kinase (DMPK). Mutant transcripts containing expanded CUG repeats form ribonuclear foci that sequester muscleblind-like (MBNL) splicing regulator proteins, key regulators of RNA splicing and me...
| Autores: | , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2026 |
| País: | España |
| Institución: | Consejo Superior de Investigaciones Científicas (CSIC) |
| Repositorio: | DIGITAL.CSIC. Repositorio Institucional del CSIC |
| OAI Identifier: | oai:digital.csic.es:10261/423798 |
| Acceso en línea: | http://hdl.handle.net/10261/423798 https://api.elsevier.com/content/abstract/scopus_id/105031753444 |
| Access Level: | acceso abierto |
| Palabra clave: | Oleic acid conjugate MBNL Antisense oligonucleotides Muscle uptake Myotonic dystrophy http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 http://metadata.un.org/sdg/14 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation Conserve and sustainably use the oceans, seas and marine resources for sustainable development |
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oai:digital.csic.es:10261/423798 |
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| dc.title.none.fl_str_mv |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| title |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| spellingShingle |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 González-Martínez, Irene Oleic acid conjugate MBNL Antisense oligonucleotides Muscle uptake Myotonic dystrophy http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 http://metadata.un.org/sdg/14 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation Conserve and sustainably use the oceans, seas and marine resources for sustainable development |
| title_short |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| title_full |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| title_fullStr |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| title_full_unstemmed |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| title_sort |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1 |
| dc.creator.none.fl_str_mv |
González-Martínez, Irene Cerro-Herreros, Estefanía Carrascosa-Sàez, Marc García-Rey, Andrea Piqueras-Losilla, Diego Colom-Rodrigo, Anna Moreno, Nerea Chakraborty, Mouli Huguet-Lachon, Aline González-Barriga, Anchel Naldaiz-Gastesi, Neia Dehesa, Martxel Díaz-Maqueda, Ana Barquero, Nuria Varela, Miguel A. López de Munain, Adolfo Eritja, Ramon Gourdon, Geneviève López-Castel, Arturo Pérez-Alonso, Manuel Llamusi, Beatriz Artero, Rubén |
| author |
González-Martínez, Irene |
| author_facet |
González-Martínez, Irene Cerro-Herreros, Estefanía Carrascosa-Sàez, Marc García-Rey, Andrea Piqueras-Losilla, Diego Colom-Rodrigo, Anna Moreno, Nerea Chakraborty, Mouli Huguet-Lachon, Aline González-Barriga, Anchel Naldaiz-Gastesi, Neia Dehesa, Martxel Díaz-Maqueda, Ana Barquero, Nuria Varela, Miguel A. López de Munain, Adolfo Eritja, Ramon Gourdon, Geneviève López-Castel, Arturo Pérez-Alonso, Manuel Llamusi, Beatriz Artero, Rubén |
| author_role |
author |
| author2 |
Cerro-Herreros, Estefanía Carrascosa-Sàez, Marc García-Rey, Andrea Piqueras-Losilla, Diego Colom-Rodrigo, Anna Moreno, Nerea Chakraborty, Mouli Huguet-Lachon, Aline González-Barriga, Anchel Naldaiz-Gastesi, Neia Dehesa, Martxel Díaz-Maqueda, Ana Barquero, Nuria Varela, Miguel A. López de Munain, Adolfo Eritja, Ramon Gourdon, Geneviève López-Castel, Arturo Pérez-Alonso, Manuel Llamusi, Beatriz Artero, Rubén |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author |
| dc.contributor.none.fl_str_mv |
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72] |
| dc.subject.none.fl_str_mv |
Oleic acid conjugate MBNL Antisense oligonucleotides Muscle uptake Myotonic dystrophy http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 http://metadata.un.org/sdg/14 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation Conserve and sustainably use the oceans, seas and marine resources for sustainable development |
| topic |
Oleic acid conjugate MBNL Antisense oligonucleotides Muscle uptake Myotonic dystrophy http://metadata.un.org/sdg/9 http://metadata.un.org/sdg/3 http://metadata.un.org/sdg/14 Ensure healthy lives and promote well-being for all at all ages Build resilient infrastructure, promote inclusive and sustainable industrialization and foster innovation Conserve and sustainably use the oceans, seas and marine resources for sustainable development |
| description |
Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansions in DM1 protein kinase (DMPK). Mutant transcripts containing expanded CUG repeats form ribonuclear foci that sequester muscleblind-like (MBNL) splicing regulator proteins, key regulators of RNA splicing and metabolism. This functional depletion leads to widespread mis-splicing and persistence of fetal transcript profiles, which underlie muscle weakness, myotonia, and muscle atrophy. In addition, miR-23b is upregulated in DM1 muscle and further represses MBNL1 translation, amplifying molecular defects. We developed chemically optimized microRNA (miRNA)-targeting antisense oligonucleotides (antimiRs) to inhibit miR-23b and restore functional MBNL1 levels. Using a multi-step screening process, we evaluated antimiRs with varying sequences, lengths, chemical modifications, and lipid conjugations. A key optimization was a 3'-oleic acid conjugation combined with specific chemical modifications, which enhanced muscle uptake and efficacy. Lead candidates showed strong activity in preclinical models (human skeletal actin [HSA]LR and DMSXL mice and human myoblasts), increasing MBNL1 levels, correcting mis-splicing, improving muscle strength, and reducing myotonia. They also exhibited efficient biodistribution to skeletal muscle, a critical DM1-affected tissue. In vitro toxicology indicated a favorable safety profile with minimal immune or renal toxicity. The antimiR mechanism was conserved in rat and pig fibroblasts. Overall, two lead antimiRs emerged as promising therapeutic candidates for DM1, with improved pharmacokinetics, tissue targeting, and safety, supporting the potential of microRNA-based approaches to correct key molecular defects in this disorder. |
| publishDate |
2026 |
| dc.date.none.fl_str_mv |
2026 2026 2026 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article http://purl.org/coar/resource_type/c_6501 Publisher's version info:eu-repo/semantics/publishedVersion |
| format |
article |
| status_str |
publishedVersion |
| dc.identifier.none.fl_str_mv |
http://hdl.handle.net/10261/423798 https://api.elsevier.com/content/abstract/scopus_id/105031753444 |
| url |
http://hdl.handle.net/10261/423798 https://api.elsevier.com/content/abstract/scopus_id/105031753444 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
American journal of human genetics https://doi.org/10.1016/j.ajhg.2026.01.016 Sí |
| dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess |
| eu_rights_str_mv |
openAccess |
| dc.publisher.none.fl_str_mv |
American Society of Human Genetics |
| publisher.none.fl_str_mv |
American Society of Human Genetics |
| dc.source.none.fl_str_mv |
reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC instname:Consejo Superior de Investigaciones Científicas (CSIC) |
| instname_str |
Consejo Superior de Investigaciones Científicas (CSIC) |
| reponame_str |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
| collection |
DIGITAL.CSIC. Repositorio Institucional del CSIC |
| repository.name.fl_str_mv |
|
| repository.mail.fl_str_mv |
|
| _version_ |
1869411214324400128 |
| spelling |
Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1González-Martínez, IreneCerro-Herreros, EstefaníaCarrascosa-Sàez, MarcGarcía-Rey, AndreaPiqueras-Losilla, DiegoColom-Rodrigo, AnnaMoreno, NereaChakraborty, MouliHuguet-Lachon, AlineGonzález-Barriga, AnchelNaldaiz-Gastesi, NeiaDehesa, MartxelDíaz-Maqueda, AnaBarquero, NuriaVarela, Miguel A.López de Munain, AdolfoEritja, RamonGourdon, GenevièveLópez-Castel, ArturoPérez-Alonso, ManuelLlamusi, BeatrizArtero, RubénOleic acid conjugateMBNLAntisense oligonucleotidesMuscle uptakeMyotonic dystrophyhttp://metadata.un.org/sdg/9http://metadata.un.org/sdg/3http://metadata.un.org/sdg/14Ensure healthy lives and promote well-being for all at all agesBuild resilient infrastructure, promote inclusive and sustainable industrialization and foster innovationConserve and sustainably use the oceans, seas and marine resources for sustainable developmentMyotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansions in DM1 protein kinase (DMPK). Mutant transcripts containing expanded CUG repeats form ribonuclear foci that sequester muscleblind-like (MBNL) splicing regulator proteins, key regulators of RNA splicing and metabolism. This functional depletion leads to widespread mis-splicing and persistence of fetal transcript profiles, which underlie muscle weakness, myotonia, and muscle atrophy. In addition, miR-23b is upregulated in DM1 muscle and further represses MBNL1 translation, amplifying molecular defects. We developed chemically optimized microRNA (miRNA)-targeting antisense oligonucleotides (antimiRs) to inhibit miR-23b and restore functional MBNL1 levels. Using a multi-step screening process, we evaluated antimiRs with varying sequences, lengths, chemical modifications, and lipid conjugations. A key optimization was a 3'-oleic acid conjugation combined with specific chemical modifications, which enhanced muscle uptake and efficacy. Lead candidates showed strong activity in preclinical models (human skeletal actin [HSA]LR and DMSXL mice and human myoblasts), increasing MBNL1 levels, correcting mis-splicing, improving muscle strength, and reducing myotonia. They also exhibited efficient biodistribution to skeletal muscle, a critical DM1-affected tissue. In vitro toxicology indicated a favorable safety profile with minimal immune or renal toxicity. The antimiR mechanism was conserved in rat and pig fibroblasts. Overall, two lead antimiRs emerged as promising therapeutic candidates for DM1, with improved pharmacokinetics, tissue targeting, and safety, supporting the potential of microRNA-based approaches to correct key molecular defects in this disorder.We thank Inmaculada Noguera for veterinary assistance at the University of Valencia SCSIE animal facility. Part of the equipment employed in this work has been funded by Generalitat Valenciana and co-financed with ERDF funds (OP ERDF of Comunitat Valenciana 2014–2020). Antibody MB1a (4A8) was provided by the MDA Monoclonal Antibody Resources. This work was supported by "la Caixa" Banking Foundation grant HR17-00268 (R.A., A.L.d.M., and G.G.), Generalitat Valenciana grants PROMETEO/2020/081 and CIPROM/2023/22 (R.A.), Instituto de Salud Carlos III grant DTS19/0128 (R.A.), Generalitat Valenciana predoctoral grant FDEGENT/2020/011 (I.G.-M.), Torres Quevedo post-doctoral fellowship PTQ2020-011110 (E.C.-H.), CDTI NEOTEC grant SNEO-20201136 (B.L.), GVA-IVACE grant IMIDTA/2021/65 (B.L.), Talent Promotion Program-Line 3 of GVA-AVI grant INNTA3/2023/16 (D.P.L.), and Instituto de Salud Carlos III grant PI21/00557 (N.N.-G. and A.L.d.M.). Illustrations were created with BioRender.Peer reviewedAmerican Society of Human GeneticsConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202620262026info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/423798https://api.elsevier.com/content/abstract/scopus_id/105031753444reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)InglésAmerican journal of human geneticshttps://doi.org/10.1016/j.ajhg.2026.01.016Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/4237982026-05-22T06:33:51Z |
| score |
15,811543 |