INTERNATIONAL CONGRESS OF
PharmacoGenetics
The impact of antisense oligonucleotides in duchenne muscular dystrophy as a personal medicine approach
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Masoume Azad Aza,1,*
1. Department of Biology, Faculty of Basic Sciences, Mashhad Branch, Islamic Azad University, Mashhad, Iran
- Introduction: Duchenne muscular dystrophy (DMD) is a severe and progressive disease characterized by muscle degeneration. The initial manifestations of the disease typically include challenges in ascending stairs, a waddling gait, and a propensity for frequent falls, with these symptoms generally emerging between the ages of 2 and 3 years. DMD is attributed to mutations in the DMD gene, which result in the disruption of the open-reading frame, leading to a deficiency in dystrophin protein and ongoing degeneration of muscle fibers. In contrast, Becker muscular dystrophy (BMD) is generally associated with a milder clinical presentation and an extended lifespan. In BMD, mutations in the same DMD gene preserve the open-reading frame, resulting in an internally truncated dystrophin protein that retains partial to substantial functionality. A promising therapeutic approach for restoring dystrophin expression involves the conversion of a DMD transcript into a BMD transcript through the application of antisense oligonucleotides (AONs), which facilitate specific exon skipping during the splicing of pre-messenger RNA (pre-mRNA). This strategy holds the potential for delivering a personalized therapy.
- Methods: In this review article, the necessary data were collected from citation and keyword databases such as PubMed, ScienceDirect, and Google Scholar. The studies reviewed focus on the effects of antisense oligonucleotides in muscular dystrophy.
- Results: Numerous antisense oligonucleotide (AON) drug candidates are currently under development for Duchenne muscular dystrophy (DMD). These AONs are single-stranded oligonucleotides that have been chemically modified to enhance their resistance to nucleases, thereby protecting the target RNA from RNaseH-mediated degradation and promoting stable binding to the target RNA. The mechanism of action of an AON is characterized by its highly sequence-specific binding to partially open pre-mRNA structures within the targeted exon, which interferes with splicing regulatory factors and/or structures. This interference facilitates exon skipping, which aims to rectify the open reading frame of the mutated DMD mRNA transcript; in approximately 70% of cases, the mutation involves the deletion of one or more exons. This process enables the production of a novel Becker muscular dystrophy (BMD)-like dystrophin protein that, despite an internal truncation, retains the essential N- and C-terminal domains necessary for its structural and signaling functions at the membranes of muscle fibers. Dystrophin is a critical component of the dystrophin-associated protein complex, with its terminal domains interacting with actin, neuronal nitric oxide synthase, β-dystroglycan, syntrophins, and dystrobrevin. In the absence of dystrophin, the integrity of this complex is compromised, resulting in increased membrane permeability, exercise-induced damage, detrimental calcium influx, and ultimately, progressive degeneration of muscle fibers and severe muscle pathology. The therapeutic objective of AON-mediated dystrophin expression is to restore the dystrophin-associated protein complex at the membrane, thereby delaying or ideally halting the progressive degeneration of muscle fibers and maintaining or enhancing muscle performance in individuals with DMD. Currently, two AON drug candidates are in clinical development for DMD: drisapersen, a 20-mer 2OMePS AON, which is undergoing phase III trials, and eteplirsen, a 30-mer PMO AON, which is in phase II trials. The target sequences within exon 51 of both candidates are highly similar, and both have demonstrated efficacy in skipping exon 51 and increasing dystrophin expression in muscle tissue from patients with relevant mutations following local and systemic administration. The primary molecular outcome measure in clinical studies involving drisapersen and eteplirsen has been the detection of novel or increased dystrophin expression in muscle biopsies, providing evidence of the targeted pharmacodynamic mechanism. Additionally, other molecular biomarkers, such as matrix metalloproteinase-9 and specific microRNAs present in serum, are currently being evaluated to assess the therapeutic effects of drug treatment in patients with DMD.
- Conclusion: AON-induced exon-skipping therapy is emerging as a form of personalized medicine for Duchenne Muscular Dystrophy (DMD). Currently, two chemically distinct drug candidates, drisapersen and eteplirsen, are in clinical development. Each candidate has unique physicochemical properties that present both advantages and disadvantages regarding safety and pharmacokinetics. Both agents have demonstrated the ability to specifically induce exon 51 skipping, thereby enhancing muscle dystrophin expression in a specific mutational subgroup of DMD patients. The integration of these therapeutic strategies is expected to facilitate the advancement of personalized treatment options for an expanding patient population.
- Keywords: Muscular Dystrophy Duchenne, Naturopathy, Genes.
