Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1

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dc.contributor.authorGonzález-Martínez, Irene
dc.contributor.authorCerro Herreros, Estefanía
dc.contributor.authorCarrascosa Sáez, Marc
dc.contributor.authorGarcía-Rey, Andrea
dc.contributor.authorPiqueras-Losilla, Diego
dc.contributor.authorColom Rodrigo, Anna
dc.contributor.authorMoreno, Nerea
dc.contributor.authorChakraborty, Mauli
dc.contributor.authorHuguet-Lachon, Aline
dc.contributor.authorGonzález-Barriga, Anchel
dc.contributor.authorNaldaiz Gastesi, Neia
dc.contributor.authorDehesa Etxebeste, Martxel Pedro
dc.contributor.authorDíaz-Maqueda, Ana
dc.contributor.author Barquero Beña, Nuria
dc.contributor.authorVarela, Miguel A.
dc.contributor.authorLópez de Munain Arregui, Adolfo
dc.contributor.authorEritja, Ramón
dc.contributor.authorGourdon, G.
dc.contributor.authorLópez Castel, Arturo
dc.contributor.authorPérez Alonso, Manuel
dc.contributor.authorLlamusi Troisi, María Beatriz
dc.contributor.authorArtero Allepuz, Rubén
dc.date.accessioned2026-04-13T13:18:35Z
dc.date.available2026-04-13T13:18:35Z
dc.date.issued2026-03-05
dc.date.updated2026-04-13T13:18:35Z
dc.description.abstractMyotonic 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.en
dc.description.sponsorshipPart 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.en
dc.identifier.citationGonzález-Martínez, I., Cerro-Herreros, E., Carrascosa-Sàez, M., García-Rey, A., Piqueras-Losilla, D., Colom-Rodrigo, A., Moreno, N., Chakraborty, M., Huguet-Lachon, A., González-Barriga, A., Naldaiz-Gastesi, N., Dehesa, M., Díaz-Maqueda, A., Barquero, N., Varela, M. A., López de Munain, A., Eritja, R., Gourdon, G., López-Castel, A., et al. (2026). Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1. American Journal of Human Genetics, 113(3), 529-547. https://doi.org/10.1016/J.AJHG.2026.01.016
dc.identifier.doi10.1016/J.AJHG.2026.01.016
dc.identifier.eissn1537-6605
dc.identifier.issn0002-9297
dc.identifier.urihttps://hdl.handle.net/20.500.14454/5622
dc.language.isoeng
dc.publisherCell Press
dc.rights© 2026 The Authors
dc.subject.otherAntisense oligonucleotides
dc.subject.otherMBNL
dc.subject.otherMuscle uptake
dc.subject.otherMyotonic dystrophy
dc.subject.otherOleic acid conjugate
dc.titleEnhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1en
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.endPage547
oaire.citation.issue3
oaire.citation.startPage529
oaire.citation.titleAmerican Journal of Human Genetics
oaire.citation.volume113
oaire.licenseConditionhttps://creativecommons.org/licenses/by-nc-nd/4.0/
oaire.versionVoR
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