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Duchenne muscular dystrophy (DMD) is a severe inherited muscle-wasting disorder that is associated with severe morbidity and mortality globally. Current treatment options have improved the quality of life of patients, but these treatments are only palliative. There is a need for more DMD treatment options. Antisense oligonucleotide (ASO) therapies have emerged as a promising personalized treatment option for patient groups that possess specific mutations. A subset of these therapies can skip over frame-disrupting exons in the DMD gene and can partially restore dystrophin production for individuals with DMD. One novel exon skipping therapy currently being investigated is brogidirsen, an exon 44 that targets ASO using a novel dual-targeting approach. This article will provide an overview of brogidirsen’s history and current clinical trial developments. It will summarize how this investigational therapy compares with other pre-clinical and clinical trial-stage ASO therapies targeting exon 44. Current advances and challenges faced by RNA-based therapies will also be discussed. Overall, brogidirsen is a promising potential addition to existing DMD treatment options, with its clinical trial results showing expression levels above that of the maximum amount of dystrophin expression achieved by current FDA- and EMA-approved exon-skipping DMD therapies. Further research will be needed to determine its overall efficacy and ability to overcome the known limitations faced by other existing ASO therapies. Full article

Duchenne muscular dystrophy (DMD) is a debilitating and fatal genetic disease affecting 1/5000 boys globally, characterized by progressive muscle breakdown and eventual death, with an average lifespan in the mid–late twenties. While no cure yet exists for DMD, gene and antisense therapies have been heavily explored in recent years to better treat this disease. Four antisense therapies have received conditional FDA approval, and many more exist in varying stages of clinical trials. These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown. Full article

Duchenne muscular dystrophy (DMD) is a lethal genetic disorder that most commonly results from mutations disrupting the reading frame of the dystrophin (DMD) gene. Among the therapeutic approaches employed, exon skipping using antisense oligonucleotides (AOs) is one of the most promising strategies. This strategy aims to restore the reading frame, thus producing a truncated, yet functioning dystrophin protein. In 2016, the Food and Drug Administration (FDA) conditionally approved the first AO-based drug, eteplirsen (Exondys 51), developed for DMD exon 51 skipping. An accurate and reproducible method to quantify exon skipping efficacy is essential for evaluating the therapeutic potential of different AOs sequences. However, previous in vitro screening studies have been hampered by the limited proliferative capacity and insufficient amounts of dystrophin expressed by primary muscle cell lines that have been the main system used to evaluate AOs sequences. In this paper, we illustrate the challenges associated with primary muscle cell lines and describe a novel approach that utilizes immortalized cell lines to quantitatively evaluate the exon skipping efficacy in in vitro studies. Full article