3 Things You Should Know About Dystrophin Dysregulation as a Therapeutic Target in Duchenne Muscular Dystrophy

Disclosures: Advisor, Site PI: Edgewise, Sarepta Therapeutics; Data Management Safety Board: Avidity Therapeutics, Octapharma; Site Subi: Biohaven, Novartis, Scholar Rock

This activity was written by PER® editorial staff based on an online activity developed with Dr Connolly.

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The staff of Physicians’ Education Resource®, LLC have no relevant financial relationships with ineligible companies.

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Release Date: March 13, 2026

Expiration Date: March 13, 2027

Learning Objectives

• Upon successful completion of this activity, you should be better prepared to:
• Identify the role of dystrophin disruption in the pathophysiology of Duchenne muscular dystrophy
• Evaluate clinical trial data for new and investigational agents for Duchenne muscular dystrophy
• Design multidisciplinary treatment plans for patients with Duchenne muscular dystrophy

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Physicians’ Education Resource®, LLC designates this enduring material for a maximum of 0.50 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER® or any company that provided commercial support for this activity.

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Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting approximately 1 in 3500 to 5000 male births worldwide. Caused by mutations in the dystrophin gene, the disease leads to progressive muscle degeneration, loss of ambulation typically by the early teenage years, and cardiorespiratory complications that significantly shorten life expectancy. Current management includes corticosteroids to slow disease progression and mutation-specific therapies such as exon-skipping agents, which restore partial dystrophin production in eligible patients. The 2024 FDA approval of the first gene transfer therapy marked a pivotal advancement, expanding options for patients regardless of mutation type. Here are 3 things you should know about treating patients with DMD.

1. Absence of dystrophin protein destabilizes muscle membranes and triggers progressive damage.

The discovery of the dystrophin gene in 1985 and subsequent isolation of the protein in 1987 by Hoffman, Brown, and Kunkel fundamentally transformed our understanding of DMD.^1,2 The dystrophin gene spans 2.5 million base pairs on the X chromosome and contains 79 coding exons, making it one of the largest human genes. Approximately one-third of DMD cases arise from de novo mutations, ensuring the disease will persist in the population despite advances in genetic counseling.³

Dystrophin functions as a critical structural protein that anchors the intracellular cytoskeleton to the extracellular matrix, stabilizing the sarcolemma during muscle contraction. If absent, the muscle cell membrane becomes fragile and susceptible to contraction-induced damage (Table 1).³ This membrane instability permits excessive calcium influx into muscle fibers, initiating a destructive cascade of events. Elevated intracellular calcium activates proteases and triggers mitochondrial dysfunction, leading to muscle fiber necrosis. The resulting cellular damage provokes chronic inflammation, which drives the replacement of functional muscle tissue with fibrosis and fat infiltration over time.

This progressive pathology explains the characteristic clinical trajectory of DMD. Affected males typically appear normal at birth but develop proximal weakness by age 3 to 5 years. Muscle biopsy and imaging studies reveal such histological abnormalities as marked fiber size variation and increased connective tissue in boys as young as 2 years. By age 10 years, substantial fatty replacement is evident on MRI, correlating with functional decline and eventual loss of ambulation.³ Understanding this pathophysiologic cascade is essential for appreciating why early intervention with gene transfer therapy—before irreversible muscle damage occurs—offers the greatest potential for clinical benefit.

2. Gene-based therapies aim to restore dystrophin expression through multiple strategies.

Gene-based therapies for DMD encompass several distinct approaches: Gene addition (delivering micro-dystrophin via adeno-associated virus [AAV] vectors), gene editing (CRISPR/Cas9-mediated correction), and utrophin modulation (upregulating a dystrophin surrogate). Each strategy offers unique advantages and challenges (Table 2^4-9).

Gene Addition Therapy

Gene transfer employs AAV vectors to deliver a truncated but functional micro-dystrophin gene directly to muscle cells. Because full-length dystrophin exceeds AAV packaging capacity, researchers have engineered micro-dystrophin constructs that retain essential functional domains.⁶

Delandistrogene moxeparvovec received FDA traditional approval in June 2024 for ambulatory patients 4 years and older.⁷ Phase 1 studies in 4 pediatric male patients established proof of concept, demonstrating 81.2% dystrophin-positive fibers and staining intensity of 96%.⁵ Four-year follow-up demonstrated sustained functional stabilization.10 However, the pivotal phase 3 EMBARK trial (N = 125) did not meet its primary end point of change in the North Star Ambulatory Assessment (NSAA) score at 52 weeks (P = .24). However, mean micro-dystrophin expression reached 34.29%, and key secondary end points favored treatment.⁸

Other gene addition programs have shown mixed results. In the CIFFREO trial, fordadistrogene movaparvovec did not meet primary or secondary end points.⁶ In the INSPIRE DUCHENNE trial of SGT-003, early positive signals including reduced muscle damage biomarkers and potential cardiac benefit were noted.⁹ GNT0004, developed using an AAV8 vector at a notably lower dose (3 × 10¹³ vg/kg), reported 2-year follow-up data (N = 5) showing robust microdystrophin expression, reduced creatine phosphokinase levels, and improved NSAA scores—with 1 patient achieving a normal NSAA score.^9,11 Pivotal phase 3 trials for GNT0004 have been approved in France and the United Kingdom. RGX-202 is also progressing toward pivotal trials.

Gene Editing

CRISPR/Cas9 technology aims to permanently correct mutations associated with DMD at the genomic level. This exon-snipping strategy could benefit up to 60% of patients, although challenges remain regarding delivery efficiency, off-target effects, and potential need for repeated treatments.⁷ Preclinical studies using compact Cas9 variants (such as SaCas9) have demonstrated successful dystrophin restoration in mdx mouse models, but human clinical trials remain in early development.¹¹

Utrophin Modulation

Utrophin, a dystrophin analogue with approximately 80% structural similarity, can partially compensate for dystrophin absence. The surrogate gene therapy rAAVrh74. MCK.GALGT2 demonstrated possible stabilization of muscle function in early-phase trials, with better responses noted among younger patients at higher doses.⁶ A prior small-molecule approach, ezutromid, was discontinued after phase 2 trials showed no significant clinical benefit, highlighting the challenge of achieving therapeutic levels of utrophin upregulation.

Safety Considerations for Gene-Based Therapies

Gene transfer carries significant risks requiring vigilant postinfusion monitoring. Adverse events follow a biphasic pattern: Acute innate immune responses within the first week followed by adaptive T-cell–mediated reactions between 4 and 10 weeks.^4,11 Hepatic dysfunction is the most common complication, occurring in 36.5% of patients during the 4- to 10-week window, requiring extended immunosuppression for at least 6 weeks.¹¹ More severe events, including myositis and myocarditis, have occurred in patients with large deletions, and fatalities have been reported in patients with advanced disease, underscoring the critical importance of patient selection.^4,9 The variability in outcomes across gene therapy trials reflects multiple factors, including the age of the patient at treatment, the specific underlying mutation, and the percentage of muscle fibers that successfully incorporate the transgene.⁴

3. Mutation-targeted therapies beyond gene transfer expand treatment options for eligible patients.

While gene-based therapies offer mutation-agnostic approaches, several mutation-specific strategies provide alternatives for patients with amenable DMD variants (Table 3).^6,12 A comprehensive understanding of these therapies is essential for designing individualized treatment plans.

Exon-Skipping Antisense Oligonucleotides

Exon skipping represents the most established mutation-specific approach for DMD. Antisense oligonucleotides induce skipping of targeted exons during pre–mRNA splicing, restoring the reading frame and enabling production of truncated but partially functional dystrophin.⁶ Four exon-skipping therapies have received FDA approval: Eteplirsen (exon 51; 2016), golodirsen (exon 53; 2019), viltolarsen (exon 53; 2020), and casimersen (exon 45; 2021). Collectively, these agents address approximately 30% of patients with DMD.

Long-term data for golodirsen demonstrated prolonged ambulation compared to natural history for up to 6 years.¹² However, the phase 3 RACER53 confirmatory trial for viltolarsen did not show significant differences versus placebo, and additional analyses are ongoing.⁶ Efficacy limitations of current exon-skipping agents relate to suboptimal tissue penetration and the burden of weekly intravenous infusions.

Peptide-Conjugated Antisense Oligonucleotides

To enhance muscle and cardiac delivery, peptide-conjugated antisense oligonucleotides were developed. Vesleteplirsen (MOMENTUM trial; exon 51) demonstrated 8-fold greater dystrophin production compared to eteplirsen; however, development was discontinued due to hypomagnesemia.⁶ Newer antibody-oligonucleotide conjugates are advancing. These include delpacibart zotadirsen, which targets exon 44 skipping mutations; it showed superior tissue penetration and sustained dystrophin restoration in early studies.

Stop Codon Readthrough Agents

Approximately 10% to 15% of patients with DMD have nonsense mutations resulting in premature stop codons. Readthrough agents enable ribosomes to bypass these stop codons, allowing translation of full-length dystrophin.6 Arbekacin is currently in phase 2 development, whereas synthetic negamycin analogues with improved safety profiles remain in preclinical stages. The expanding therapeutic landscape underscores the importance of comprehensive genetic testing to identify mutation-specific treatment eligibility and the need for multidisciplinary teams capable of navigating complex treatment decisions across a patient’s lifespan.

REFERENCES

1. Kunkel LM, Monaco AP, Middlesworth W, Ochs HD, Latt SA. Specific cloning of DNA fragments absent from the DNA of a male patient with an X chromosome deletion. Proc Natl Acad Sci U S A. 1985;82(14):4778-4782. doi:10.1073/pnas.82.14.4778

2. Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51(6):919-928. doi:10.1016/0092-8674(87)90579-4

3. Duan D, Goemans N, Takeda S, Mercuri E, Aartsma-Rus A. Duchenne muscular dystrophy. Nat Rev Dis Primers. 2021;7(1):13. doi:10.1038/s41572-021-00248-3

4. Bönnemann CG, Belluscio BA, Braun S, et al. Dystrophin immunity after gene therapy for Duchenne muscular dystrophy. N Engl J Med. 2023;388(24):2294-2296. doi:10.1056/NEJMc2212912

5. Mendell JR, Sahenk Z, Lehman K, et al. Assessment of systemic delivery of rAAVrh74.MHCK7.micro-dystrophin in children with Duchenne muscular dystrophy: a nonrandomized controlled trial. JAMA Neurol. 2020;77(9):1122-1131. doi:10.1001/jamaneurol.2020.1484

6. Yao S, Chen Z, Yu Y, et al. Current pharmacological strategies for Duchenne muscular dystrophy. Front Cell Dev Biol. 2021;9:689533. doi:10.3389/fcell.2021.689533

7. FDA expands approval of gene therapy for patients with Duchenne muscular dystrophy. News release. FDA. June 20, 2024. Accessed January 14, 2026. https://www.fda.gov/news-events/press-announcements/fda-expands-approval-gene-therapy-patients-duchenne-muscular-dystrophy

8. Mendell JR, Muntoni F, McDonald CM, et al. AAV gene therapy for Duchenne muscular dystrophy: the EMBARK phase 3 randomized trial. Nat Med. 2025;31(1):332-341. doi:10.1038/s41591-024-03304-z

9. Kurshakova EV, Levchenko OA, Smirnikhina SA, Lavrov AV. The promise and pitfalls of AAV-mediated gene therapy for Duchenne muscular dystrophy. Curr Issues Mol Biol. 2025;47(12):1058. doi:10.3390/cimb47121058

10. Mendell JR, Proud CM, Lehman KJ, et al. Long-term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: a phase 1/2a nonrandomized trial. Muscle Nerve. 2024;69(1):93-98. doi:10.1002/mus.27955

11. Manini A, Abati E, Nuredini A, Corti S, Comi GP. Adeno-associated virus (AAV)-mediated gene therapy for Duchenne muscular dystrophy: the issue of transgene persistence. Front Neurol. 2022;12:814174. doi:10.3389/fneur.2021.814174

12. Muntoni F, Mercuri E, Lehman KJ, et al. Long-term ambulatory outcomes in patients with Duchenne muscular dystrophy treated with golodirsen: 6-year analysis. Neuromuscul Disord. 2023;33(suppl 1):S170. doi:10.1016/j.nmd.2023.07.444