The complexity of dystrophin transcription and processing: implications of transcript imbalance on dystrophin gene targeting strategies.

Duchenne muscular dystrophy (DMD) is a rare genetic disorder affecting male children, characterized by progressive muscle wasting and weakness. It is a fatal disease, typically leading to death between the ages of 20 and 40, and currently, there is no effective cure. DMD is caused by mutations, most commonly large deletions, in the DMD gene, one of the largest genes in the human genome. This gene also exhibits a distinctive feature known as transcript imbalance, which refers to the unbalance expression of the transcript along its length, with the 5' end being more abundantly expressed than the 3' end. Although transcript imbalance was first described in 1995, it remains a poorly understood phenomenon with many unanswered questions. This review highlights the need for a deeper investigation into transcript imbalance, which has not yet received sufficient attention from the scientific community or from sponsors involved in DMD translational research. Understanding and addressing this phenomenon is critical not only for refining antisense oligonucleotide (AON) therapies and enhancing their therapeutic efficacy, but also for developing innovative strategies that improve DMD transcript targeting and muscle delivery.