Researchers say an overlooked feature of Duchenne muscular dystrophy (DMD) may be quietly limiting the impact of today’s most promising genetic treatments, according to a review published recently in Neuromuscular Disorders.
The problem, known as transcript imbalance, means that the dystrophin gene’s RNA is not evenly produced from start to finish. This imbalance appears to be common in DMD, present to a lesser degree in Becker muscular dystrophy and detectable even in healthy muscle. It may help explain why some therapies restore less dystrophin protein than expected.
DMD is caused by mutations in the DMD gene, one of the largest genes in the human genome. For decades, scientists have known that the beginning of the dystrophin RNA is more abundant than the end, but why this happens and how much it matters has remained unclear.
“[A] comprehensive investigation into the reciprocal influence of genetic treatments on transcript imbalance — and vice versa — is critical at this stage of DMD therapy development and implementation,” explained the authors of this review.
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Studies in patients and animal models show that transcript imbalance varies by muscle type and mutation location. In Becker muscular dystrophy, which allows production of a shorter but partly functional dystrophin protein, higher RNA balance is moderately linked with higher protein levels. In DMD, where mutations often trigger destruction of the RNA, this relationship breaks down, suggesting additional forces are at work.
Several explanations have been proposed. Making dystrophin RNA takes about 16 hours, but the finished message may last only a few hours before being degraded. In dystrophic muscle, RNA production appears reduced, and much of the RNA becomes trapped in the cell nucleus. About 90% of dystrophin RNA stays in the nucleus in DMD samples compared with about 40% in healthy muscle, limiting how much reaches the cell machinery that makes protein.
This matters for patients because current exon-skipping drugs, called antisense oligonucleotides, depend on enough full-length RNA being available. Four such drugs have received accelerated FDA approval, but all restore dystrophin to relatively low levels. If skipped RNA never becomes complete or export-ready, measured success in the lab may overstate real protein gains in muscle.
Experts argue that future trials must measure dystrophin RNA more carefully and consistently. New tools such as long-read sequencing and spatial transcriptomics may help link RNA changes directly to protein restoration. For patients, this research could lead to better-designed therapies, clearer expectations and ultimately treatments that deliver more meaningful muscle protection.
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