Fighting for every beat: cardiac therapies in Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a severe, progressive genetic disorder caused by mutations in the DMD gene, resulting in the absence of dystrophin—a key structural protein at the sarcolemma. As the disease progresses, cardiac involvement becomes a leading cause of morbidity and mortality. By adolescence or early adulthood, many patients develop dilated cardiomyopathy and arrhythmias. Like skeletal muscle, cardiac muscle in DMD patients lacks dystrophin and undergoes similar degenerative changes, ultimately leading to ventricular dilation, systolic dysfunction, and heart failure. Early detection and proactive management of cardiac dysfunction are essential for optimizing outcomes. Despite significant advances and decades of research, a definitive cure for DMD remains elusive. In recognition of World Duchenne Awareness Day, this review highlights current and emerging therapeutic strategies with the potential to transform cardiac care in DMD and improve the lives of those affected.

Maintext

Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is the most common and one of the most severe forms of inherited muscular dystrophies [1]with an estimated global incidence of approximately 1 in 5,000 live male births [2]. It is an X-linked recessive disorder caused by mutations in the DMD gene, which encodes dystrophin, a large cytoskeletal protein critical for maintaining the structural integrity of striated muscle cells, including both skeletal and cardiac muscle [3]. Dystrophin plays a central role in stabilizing the sarcolemma by anchoring the intracellular cytoskeleton to the extracellular matrix via the dystrophin-associated glycoprotein complex [4, 5]. This linkage is essential for efficient force transmission during muscle contraction [6]. In the absence of functional dystrophin, the dystrophin-associated glycoprotein complex is disrupted, weakening the sarcolemmal membrane and rendering it highly susceptible to mechanical stress. This increased fragility results in repeated cycles of muscle fiber damage and degeneration, triggering inflammation, necrosis, and ultimately replacement of muscle tissue with fibrotic and adipose tissue [7]. Recognizing DMD as one of the most common rare genetic disorders in children, the United Nations has designated 7 September—currently observed as World Duchenne Awareness Day. Clinically, DMD is characterized by progressive muscle weakness, typically manifesting in early childhood with difficulty walking, frequent falls, and delayed motor milestones [3]. As the disease advances, cardiac involvement becomes a major cause of morbidity and mortality, with many patients developing dilated cardiomyopathy and arrhythmias by adolescence or early adulthood [8, 9]. Cardiac muscle, like skeletal muscle, lacks dystrophin in DMD, and is therefore prone to the same degenerative processes, leading to ventricular dilation, systolic dysfunction, and heart failure [10]. Despite improvements in respiratory care and corticosteroid therapy, cardiac complications remain a significant therapeutic challenge in DMD [11]. Early recognition and management of cardiac dysfunction are crucial for improving patient outcomes.

In DMD, early signs of muscle weakness typically present between the ages of three and five years [3]. The weakness initially affects proximal muscle groups, such as those in the pelvic and shoulder girdles, leading to difficulties with tasks such as standing up from the floor, climbing stairs, and walking. As the disease progresses, weakness extends to distal skeletal muscles and ultimately affects both the limbs and axial musculature. Without timely and comprehensive intervention, most individuals with DMD lose the ability to ambulate independently by the age of 10 to 12 years. Historically, the clinical focus in DMD was on skeletal muscle deterioration, as early loss of mobility and respiratory failure—caused by weakness of the diaphragm and intercostal muscles—were the most immediate life-limiting complications. These complications often masked early signs of cardiac involvement, which were under-recognized and underdiagnosed [12]. However, over the past two decades, significant advances in multidisciplinary care have transformed the clinical trajectory of DMD. The implementation of non-invasive ventilation [13] corticosteroid therapy [14]and targeted muscle-preserving treatments [15] has led to marked improvements in mobility, respiratory function, and overall survival. As a result, more patients are now surviving into adolescence and adulthood, shifting the natural history of the disease and revealing cardiac complications as a major contributor to morbidity and mortality in the DMD population. Cardiomyopathy in DMD is now recognized as a progressive and nearly universal feature of the disease [16]. It typically begins as subclinical myocardial involvement during early childhood and progresses to overt dilated cardiomyopathy and heart failure with advancing age [17]. Recent studies estimate that approximately 25% of boys with DMD show signs of cardiomyopathy by the age of 6, with prevalence increasing to nearly 60% by age 10. By adulthood, the majority of individuals—over 90% of men older than 18 years [10]—demonstrate significant cardiac dysfunction, even in the absence of skeletal muscle activity.

Pathogenesis

This emerging cardiac burden underscores the urgent need for early screening, regular cardiac monitoring, and cardioprotective interventions in the standard care protocol for DMD patients. It also highlights the importance of integrating cardiac-targeted therapies into the broader therapeutic strategy, as preserving cardiac function is now critical for improving both quality of life and survival in this expanding patient population [18]. The development of dilated cardiomyopathy in DMD is the result of a complex interplay of molecular, structural, and functional abnormalities. While significant progress has been made in understanding the underlying mechanisms, the complete pathophysiology of DMD-associated cardiomyopathy remains incompletely elucidated. A defining biochemical hallmark of DMD is the elevation of plasma creatine kinase (CK) levels [19] which reflects ongoing sarcolemmal membrane damage [20]. The loss of dystrophin, a critical structural protein, compromises the integrity of the dystrophin-associated glycoprotein complex, destabilizing the sarcolemma and impairing mechanical force transmission during muscle contraction. This structural vulnerability renders cardiac and skeletal myocytes susceptible to contraction-induced membrane micro-ruptures, which result in increased permeability and the leakage of cytoplasmic components, such as CK, into the circulation. One major consequence of membrane destabilization is the abnormal influx of extracellular calcium ions [21]. This unregulated calcium entry leads to calcium overload within the cardiomyocytes, which in turn activates proteolytic enzymes, such as calpains, and promotes oxidative stress, mitochondrial dysfunction, and ultimately myocyte necrosis or apoptosis [22]. While the precise mechanisms responsible for this increased membrane permeability and calcium dysregulation remain under investigation, it is widely accepted that calcium mishandling plays a central role in disease progression. In the early stages of DMD cardiomyopathy, compensatory mechanisms are observed, particularly in animal models. These include an increase in calcium transient amplitude, enhanced sarcoplasmic reticulum calcium load, and elevated diastolic calcium leak, which may temporarily sustain cardiac contractility despite underlying damage [23]. However, these adaptations come at the cost of energetic inefficiency and increased cellular stress, gradually exhausting the myocardium’s functional reserve [24]. As the disease advances into the decompensated stage, these compensatory processes fail, giving rise to overt dilated cardiomyopathy. This stage is marked by ventricular dilation, thinning of the cardiac walls, and a significant decline in systolic function. Additionally, a reduction in calcium transient amplitude, impaired excitation-contraction coupling, and progressive myocardial fibrosis further deteriorate cardiac performance [25]. Arrhythmias, both atrial and ventricular, become more prevalent and contribute significantly to the risk of sudden cardiac death in these patients [26]. Overall, DMD-associated cardiomyopathy reflects a continuum of pathophysiological changes—from early subclinical dysfunction marked by membrane instability and calcium mishandling, to advanced heart failure characterized by structural remodeling, fibrosis, and electrical instability. These insights underscore the need for early intervention strategies aimed at preserving calcium homeostasis, stabilizing the sarcolemma, and protecting mitochondrial function to slow or prevent the progression of cardiac disease in DMD.

Cardiac therapies

To address DMD, novel genetic and molecular therapies are being developed with the aim of either restoring dystrophin function or compensating for its loss [15]. Although cardiac complications have become the primary determinants of survival in patients with DMD, most clinical trials continue to evaluate therapeutic efficacy based predominantly on improvements in skeletal muscle function. Consequently, many of these treatments show limited or no efficacy in mitigating cardiac involvement. Given the critical role of cardiac pathology in determining clinical outcomes, this article reviews emerging therapeutic strategies targeting cardiac manifestations in DMD.

The absence of curative therapies for DMD has prompted a growing focus on small molecule–based treatments designed to alleviate cardiac complications and slow disease progression. Given the high prevalence of cardiomyopathy in DMD and its role as a leading cause of morbidity and mortality, targeting the heart has become an essential aspect of comprehensive disease management [27, 28]. Currently, three main classes of small molecules are utilized to manage cardiac symptoms in DMD patients: angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), which reduce cardiac afterload and mitigate fibrosis; beta-adrenergic blockers, which decrease heart rate and myocardial oxygen demand to prevent further cardiac deterioration; and mineralocorticoid receptor antagonists, which act to counter fibrosis and improve ventricular function. These pharmacological agents are typically used in combination and initiated early in the disease course to preserve cardiac function and delay the onset of heart failure. While these treatments do not address the underlying genetic defect, they play a crucial role in symptomatic management and are considered standard of care in DMD-related cardiomyopathy.

Genetic therapy represents a highly promising avenue for the treatment of DMD, with the primary objective of restoring the production of functional dystrophin protein in affected muscle tissue. This therapeutic strategy aims to either correct the underlying mutation in the DMD gene or introduce a new, functional copy of the gene into the patient’s cells. Nonsense readthrough therapy targets DMD patients with nonsense mutations—about 10% of cases—where a premature stop codon halts dystrophin production. This approach uses compounds to allow the ribosome to bypass the faulty stop signal and continue translation, potentially restoring functional dystrophin [29]. Gentamycin showed early promise in mice but failed in human trials [30]. Exon skipping is a promising therapeutic strategy for DMD that aims to restore the disrupted reading frame of the DMD mRNA, allowing production of a shortened but functional dystrophin protein [31]. This is typically achieved using antisense oligonucleotides (AOs), such as phosphorodiamidate morpholino oligomers (PMOs), which bind to specific splice sites and promote the exclusion of targeted exons. Several FDA-approved PMO-based drugs—eteplirsen (exon 51), golodirsen and viltolarsen (exon 53), and casimersen (exon 45)—have shown modest improvements in skeletal muscle function, but limited efficacy in the heart [31]. To address delivery challenges, particularly in cardiac tissue, peptide-conjugated PMOs (PPMOs) are under investigation [32]. However, across all strategies, consistent improvement in cardiac function remains an unmet challenge, highlighting the need for optimized delivery and safety in future clinical development. Ataluren (Translarna), developed to improve efficacy and reduce toxicity, is approved in Europe but not by the FDA [33]. Clinical trials have shown modest motor improvements and delayed disease progression, though its impact on cardiac function remains unclear. Gene editing technologies, such as CRISPR/Cas9, are designed to target and repair specific mutations within the native DMD gene, thereby restoring its ability to produce full-length or partially functional dystrophin. This approach has shown encouraging results in preclinical models and holds potential for personalized, mutation-specific interventions [34–37]. Gene replacement therapy, on the other hand, involves the delivery of a micro- or mini-dystrophin gene—engineered to fit within the packaging limits of viral vectors, most commonly adeno-associated virus (AAV) vectors [38–42]. These shortened versions of the gene encode truncated forms of dystrophin that retain essential functional domains and can provide significant clinical benefit. Despite the progress, several challenges remain, including immune responses to viral vectors, efficient delivery to cardiac and skeletal muscle, and long-term expression and safety.

Innovative therapies

The years ahead are certain to bring new avenues of discovery and renewed hope for individuals living with DMD. As research continues to advance, innovative therapies—from gene and cell-based treatments to pharmacological and regenerative strategies—are steadily reshaping our understanding of how to manage and potentially slow the progression of this devastating disease. While current treatments provide only limited relief, ongoing clinical trials and scientific breakthroughs offer promising signs that more effective and personalized interventions are on the horizon. With a growing commitment from the medical and research communities, as well as increasing advocacy and awareness, the future holds real potential for improved quality of life and extended survival for those afected by DMD. Here are several innovative therapeutic approaches that represent the forefront of DMD research and development—each of which will need to be followed closely as they progress through preclinical and clinical evaluation. These emerging treatments span a wide range of strategies, from gene replacement therapies to cell-based interventions and pharmacological approaches targeting cardiac muscle preservation and inflammation. As these therapies move forward, it will be essential to monitor not only their efficacy but also their safety profiles, immune responses, durability of benefit, and real-world applicability. The progress of these innovations could ultimately redefine the treatment landscape for DMD, making it vital for clinicians, researchers, and patient communities to stay informed and engaged in their development.

a. Pharmacological therapy

To counter the loss of sarcolemmal integrity, researchers have investigated the use of synthetic amphiphilic copolymers—most notably poloxamer 188 (P188)—as a membrane-stabilizing therapy. P188 works by selectively integrating into sites of membrane damage, where mechanical stress or micro-tears expose the hydrophobic interior of the lipid bilayer [43]. Molecular simulations have illustrated this mechanism, showing how P188 localizes to and seals membrane disruptions, thereby reducing ion and molecule leakage. In vitro studies have confirmed that P188 effectively decreases membrane permeability in dystrophic muscle cells, and these protective effects have been echoed in preclinical models [44]. In both mdx mice and dystrophic dogs, P188 treatment led to reduced inflammation and myocyte necrosis, as well as improved cardiac and skeletal muscle function. Treated animals demonstrated better cardiac performance and structural preservation, reinforcing the potential of membrane repair as a therapeutic strategy [45–48]. These encouraging results have paved the way for a first-in-human clinical trial now underway to evaluate the safety and efficacy of P188 in DMD patients. If successful, P188 could represent a novel, non-genetic pharmacological approach that supports muscle cell survival and addresses cardiac complications—an area of urgent need in the DMD population.

b. Cell therapy

Deramiocel is an investigational cell-based therapy derived from cardiac mesenchymal stem cells (MSCs), which are known for their ability to secrete regenerative and anti-inflammatory factors that support muscle repair. Developed by Capricor Therapeutics, Deramiocel aims to harness these regenerative properties to reduce inflammation, promote tissue healing, and potentially regenerate damaged muscle tissue in individuals with DMD, particularly targeting heart muscle disease [49]. The therapy has gained significant regulatory momentum, with the U.S. Food and Drug Administration (FDA) granting it priority review — a designation that expedites the agency’s decision-making process. Deramiocel is currently being evaluated in the Phase 3 HOPE-3 clinical trial (NCT05126758), which includes DMD patients aged 10 and older who receive either the therapy or placebo quarterly for one year.

c. Gene therapy

Gene therapy using adeno-associated virus (AAV) to deliver microdystrophin (µdys) genes has emerged as a promising strategy for treating DMD [38–42]. µdys constructs are designed to be compact enough to fit within AAV vectors while retaining the essential functional domains of full-length dystrophin. Several µdys-based gene replacement therapies are currently in clinical trials, evaluating both safety and efficacy. Among the most notable advances is the FDA approval of ELEVIDYS (delandistrogene moxeparvovec) by Sarepta Therapeutics—the first gene therapy approved for DMD [50]. Despite this milestone, significant safety concerns have emerged. Reports of serious cardiac events, including myocarditis, have surfaced in ongoing trials, likely due to immune responses targeting either the AAV vector or the µdys protein [51, 52]. These concerns intensified following Pfizer’s recent disclosure of an unexplained death occurring one year after treatment in the DAYLIGHT study (NCT05429372). Additionally, a recent report revealed that the Phase 3 trial of ELEVIDYS [52] failed to demonstrate meaningful clinical benefit over standard care, suggesting that immune-mediated interference may be compromising therapeutic efficacy. Other gene therapy trials using similar µdys constructs, such as GNT-016-MDYF, are underway and warrant close observation. These studies may offer crucial insights into the broader potential—and limitations—of µdys-based therapies. Recent developments in Sarepta Therapeutics’ gene therapy programs have raised significant safety concerns following the deaths of three patients who experienced acute liver failure after receiving investigational gene therapy for DMD. These fatalities have prompted increased scrutiny from regulatory bodies and the scientific community, as they highlight the potential risks associated with high-dose systemic delivery of AAV-based vectors. While Sarepta’s gene therapy has shown promise in improving motor function, the occurrence of severe hepatotoxicity underscores the need for better understanding of vector dose thresholds, patient susceptibility, and long-term safety. Ongoing investigations aim to determine the root causes of these adverse events and assess whether patient-specific factors, such as preexisting liver conditions or immune responses, contributed to the outcome. Rigorous evaluation of both efficacy and adverse events, particularly immune-related complications [53–54]is essential. Such comparative data will be critical for refining future therapeutic designs, optimizing treatment protocols, and informing regulatory and clinical decision-making. In a disease as complex and heterogeneous as DMD, building a robust, evidence-based treatment framework requires careful scrutiny of emerging clinical data.

Conclusion

While DMD remains a devastating and progressive neuromuscular disorder with no definitive cure, significant strides are being made in the development of therapeutic approaches aimed at slowing disease progression and improving quality of life. Gene therapy continues to offer immense promise, particularly through strategies that aim to restore dystrophin expression or modulate downstream pathological pathways. However, recent clinical findings have underscored the complexity of these approaches, revealing challenges such as immune responses to viral vectors or therapeutic proteins, limitations in delivery efficiency, and questions about the durability of treatment effects. These outcomes highlight the urgent need for a more comprehensive understanding of DMD pathophysiology, improved gene delivery technologies, and careful evaluation of long-term safety and efficacy. In parallel, complementary strategies—including anti-inflammatory agents, membrane-stabilizing compounds, and cell-based therapies—are being explored to address the multifaceted nature of the disease. Together, these evolving approaches reflect a growing commitment to transforming DMD from a fatal diagnosis into a manageable condition, offering hope for a future where more effective and personalized treatments become a reality. This review encouraged stakeholders to raise awareness of the specific challenges and needs of individuals and families affected by DMD, with the aim of fostering greater understanding, empathy, and global solidarity.

Abbreviations

DMD

Duchenne muscular dystrophy

CK

Creatine kinase

MSCs

Mesenchymal stem cells

AAV

Adeno-associated virus

FDA

U.S. Food and Drug Administration

µdys

Microdystrophin

Author contributions

The author drafted the work AND to approved the submitted version AND agreed to be personally accountable for the author’s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work.

Funding

The work was funded by the Institut National de la Santé et de la Recherche Médicale, Sorbonne Université and the Association Française contre les Myopathies.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

As this is review article, this is not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.