Publications

Latest publication 02/20/2026

Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotide

Summary Myotonic dystrophy type 1 (DM1) is a multisystemic disorder caused by CTG repeat expansions in DM1 protein kinase ( DMPK ). Mutant...

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    [title] => Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotide
    [paragraph] => Enhanced muscle uptake of chemically optimized miR-23b antisense oligonucleotides as lead compounds for myotonic dystrophy type 1
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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

 Lab

Journal
The American Journal of Human Genetics
Abstract
Summary
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.

Keywords/Topics
antisense oligonucleotides; MBNL; myotonic dystrophy; oleic acid conjugate; muscle uptake
BIOSEB Instruments Used:
Grip strength test (BIO-GS4)
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An easy way to objectively quantify the muscular strength of mice and rats, and to assess the effect of drugs, toxins, muscular (i.e. myopathy) and neurodegenerative diseases on muscular degeneration. It is widely used in conjunction with the ROTAROD motor coordination test: a normally coordinated rodent will show a decreased latency to fall off the rotating rod if its muscular strength is low. The Grip Strength Test is a must for your research on activity, motor control & coordination, and is particularly well suited for studies on Parkinson's & Huntington's disease.
New features GS4 - 2023: Color display with permanent backlight screen for easier reading, reset by footswitch, Improved battery time, Larger data memory of 500 values, Animal counter, USB port (charging/data transfer)

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