Molecular therapy : the journal of the American Society of Gene TherapyMar 25, 2026

Increasing Utrophin Using Gene Editing May Improve Duchenne Muscular Dystrophy

CRISPR Gene Editing Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 27, 2026

Abstract

Essence

CRISPR disruption of a Let-7c binding site in UTRN suggests a mutation-independent way to boost utrophin and improve DMD-like muscle function.

Evidence

Preclinical gene-editing experiments in DMD myoblasts, a 3D human skeletal muscle model, and mdx mice tested Cas9/gRNA disruption of repressor sites and found utrophin upregulation with functional and histologic gains.

Caveat

The work remains in cell, engineered tissue, and mouse models, so patient-level efficacy and systemic-delivery safety are not established.

Simplified

Duchenne muscular dystrophy is a lethal neuromuscular disorder caused by loss of dystrophin. Upregulating utrophin, a dystrophin paralogue, is a promising gene therapy approach. Here, we present a CRISPR-Cas9-based strategy to enhance utrophin expression by disrupting repressor binding sites. Using a Cas9/gRNA ribonucleoprotein complex we disrupted several such sites in DMD myoblasts and identified micro-RNA Let-7c binding site as effective in relieving repression of the UTRN gene. Interestingly, Cas9-generated indels were as effective as the complete removal of Let-7c binding site in upregulating UTRN expression, with minimal off-target effects. In a three-dimensional tissue-engineered human skeletal muscle model of DMD, this editing strategy resulted in significant utrophin upregulation and functional improvements of calcium dysregulation and muscle contraction. Finally, in mdx mice, local or systemic delivery of recombinant adeno-associated viruses encoding Cas9 and gRNA targeting the Let-7c binding site resulted in utrophin upregulation and amelioration of muscle histopathology and function. These findings provide the foundations for a mutation-independent, potentially universal gene editing therapeutic strategy for DMD.