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Publications

Journal Article Ahead of print

PubMed: 41722569 DOI: 10.1016/j.ajhg.2026.01.016

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

Am J Hum Genet

Authors: Irene González-Martínez, Estefanía Cerro-Herreros, Marc Carrascosa-Sàez, Andrea García-Rey, Diego Piqueras-Losilla, Anna Colom-Rodrigo, Nerea Moreno, Mouli Chakraborty, Aline Huguet-Lachon, Anchel González-Barriga, Neia Naldaiz-Gastesi, Martxel Dehesa, Ana Díaz-Maqueda, Nuria Barquero, Miguel A Varela, Adolfo López de Munain, Ramon Eritja, Geneviève Gourdon, Arturo López-Castel, Manuel Pérez-Alonso, Beatriz Llamusi, Rubén Artero

Affiliations

  • Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), University of Valencia, Av. Dr. Moliner 50, 46100 Valencia, Spain; INCLIVA Biomedical Research Institute, Av. Menendez Pelayo 4, 46010 Valencia, Spain; CIBERER, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain.
  • Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), University of Valencia, Av. Dr. Moliner 50, 46100 Valencia, Spain; INCLIVA Biomedical Research Institute, Av. Menendez Pelayo 4, 46010 Valencia, Spain.
  • ARTHEx Biotech, Centro de Investigación Príncipe Felipe (CIPF), Valencia, Spain.
  • Sorbonne Université, INSERM, Institut de Myologie, Centre de Recherche en Myologie, Paris, France.
  • Biodonostia-BioGipuzkoa, Neurosciences Area, Neuromuscular Diseases Laboratory, San Sebastian, Spain; Department of Neurology, Hospital Universitario Donostia, OSAKIDETZA, San Sebastian, Spain; CIBERNED, ISCIII, Madrid, Spain.
  • Department of Paediatrics, Institute of Developmental and Regenerative Medicine (IDRM), University of Oxford, Oxford, UK; MDUK Oxford Neuromuscular Centre, University of Oxford, Oxford, UK.
  • Biodonostia-BioGipuzkoa, Neurosciences Area, Neuromuscular Diseases Laboratory, San Sebastian, Spain; Department of Neurology, Hospital Universitario Donostia, OSAKIDETZA, San Sebastian, Spain; CIBERNED, ISCIII, Madrid, Spain; Department of Neurosciences, University of the Basque Country, San Sebastian, Spain; Faculty of Health Sciences, University of Deusto, Bilbao, Spain.
  • Nucleic Acids Chemistry Group, Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain; Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Barcelona, Spain.
  • Human Translational Genomics Group, University Institute for Biotechnology and Biomedicine (BIOTECMED), University of Valencia, Av. Dr. Moliner 50, 46100 Valencia, Spain; INCLIVA Biomedical Research Institute, Av. Menendez Pelayo 4, 46010 Valencia, Spain; CIBERER, ISCIII, Av. Monforte de Lemos 3-5, 28029 Madrid, Spain.

Abstract

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.

MeSH

Oligonucleotides, Antisense, Safety, Muscles, Myotonic Dystrophy, Oligonucleotides, Micrornas, Multiple Chronic Conditions, Myotonia, Tissues