RARE DISEASE
Duchenne and Becker muscular dystrophy
Duchenne and Becker muscular dystrophy
Duchenne and Becker muscular dystrophy
Synonyms: Severe dystrophinopathy, Duchenne and Becker type
Synonyms: Severe dystrophinopathy, Duchenne and Becker type
Synonyms: Severe dystrophinopathy, Duchenne and Becker type
Drug discovery
7
drugs
With orphan designations
Overview
Duchenne (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive dystrophinopathies causing progressive proximal muscle weakness, cardiomyopathy, and respiratory decline. DMD presents in early childhood with rapid progression to loss of ambulation by adolescence, while BMD manifests later with slower progression. Both result from DMD gene mutations causing dystrophin deficiency (<5% in DMD vs partial/abnormal in BMD). Diagnosis combines clinical assessment, elevated CK levels, genetic testing, and muscle biopsy dystrophin analysis [1][16].
Therapies
Glucocorticoids: First-line (prednisone/deflazacort) to delay functional decline and cardiomyopathy [1][3]
Exon-skipping: Eteplirsen (exon 51), golodirsen/viltolarsen (exon 53) for mutation-specific dystrophin restoration [3][13]
Emerging approaches: Gene therapy (microdystrophin AAV vectors), stop codon readthrough agents (ataluren), and cardiomyopathy management with ACE inhibitors/beta-blockers [8][18]
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
303 drug discovery papers about Duchenne and Becker muscular dystrophy, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
303 drug discovery papers about Duchenne and Becker muscular dystrophy, with 4 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2026-09-15 | Development of an AAV-Encoded Adenine Base Editor for Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by out-of-frame mutations in the DMD gene, most commonly large deletions or duplications, as well as nonsense and splice site mutations, that result in the absence of functional dystrophin protein. These mutations lead to progressive skeletal and cardiac muscle failure. In particular, exon 52 of the DMD gene represents a mutational hotspot in DMD patients. Deletion of exon 52 ( DMD Δ52) disrupts the reading frame, leading to premature termination of translation. Here, we used a dual recombinant adeno-associated virus (rAAV) system employing an intein-mediated split strategy to deliver ABE8e using the PAM-less SpRY Cas9 nickase for adenine base editing of splice acceptor sites (SAS) in the dystrophin gene. Targeting the SAS of exon 51 or exon 53 in a DMD Δ52 background aims to induce exon skipping, thereby restoring the open reading frame, in effect converting the severe DMD phenotype into a milder Becker muscular dystrophy (BMD)-like phenotype. We systematically screened sgRNAs in porcine kidney fibroblasts and human embryonic kidney cells (HEK293T), identifying a guide RNA targeting the SAS of exon 53 as the most effective candidate with high on-target editing efficacies and minimal bystander editing. In human DMDΔ52 iPSC-derived cardiomyocytes cultivated as 2D monolayers, high editing efficiencies were achieved with the optimized 1:2 ratio of N-Terminus to C-Terminus. Functional assessment in 3D engineered heart patches revealed a trend toward normalization of the arrhythmic DMD phenotype with an increase in the effective refractory period (ERP) and a reduction in arrhythmic load compared with untreated DMD patches, despite lower editing efficacy in the 3D setting. These findings suggest that even modest levels of base editing-mediated exon skipping may ameliorate the DMD cardiac phenotype toward a BMD-like state, supporting the translational potential of this dual rAAV base editing approach for DMD cardiomyopathy.
2026-06-05 | Gene editing restores full-length dystrophin and affects iron homeostasis in hiPSC-derived cardiomyocytes from Becker Muscular Dystrophy patients
Becker Muscular Dystrophy (BMD) is caused by in-frame mutations in the DMD gene, leading to the production of internally truncated but partially functional dystrophin. Although cardiac involvement is a major contributor to disease burden in BMD, the cellular mechanisms driving cardiomyopathy remain incompletely understood. While emerging evidence suggests that iron imbalance may contribute to oxidative stress and mitochondrial dysfunction in muscular dystrophies, its role in BMD-associated cardiomyopathy has not been defined. Building on our previous findings of dysregulated iron homeostasis in dystrophin-deficient cardiomyocytes from Duchenne muscular dystrophy (DMD), we investigated whether similar alterations are present in BMD using patient-specific and genome-corrected hiPSC-CM models. HiPSC lines derived from two BMD patients and their CRISPR/Cas9-corrected isogenic controls displayed normal karyotype, pluripotency, and efficient differentiation into cardiomyocytes (hiPSC-CMs). BMD hiPSC-CMs showed elevated ROS levels and decreased cytoplasmic and mitochondrial labile iron pools, accompanied by reduced expression of mitoNEET ( CISD1 ), a regulator of mitochondrial iron handling. We also detected changes in the expression of genes involved in iron storage ( FTH1 ), uptake ( TFRC ), and export ( SLC40A1 ), suggesting a dysregulation of iron trafficking. Importantly, correction of DMD mutation by CRISPR/Cas9 gene editing reversed the effects observed in BMD cardiomyocytes. These results extend our previous observations in DMD to BMD cardiomyocytes and suggest that full-length dystrophin is essential for maintaining cardiac iron homeostasis.
2026-03-16 | Molecular Mechanisms and Therapeutic Strategies in Heart Failure Due to Dystrophin Deficiency: A Comprehensive Review
Dystrophin deficiency is the core pathological feature of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Indeed, a deficiency in dystrophin results in the progressive degeneration of skeletal muscle and severely compromises the structure and function of cardiomyocytes, eventually leading to dilated cardiomyopathy and heart failure. Thus, this review provides an in-depth analysis of the molecular mechanisms underlying dystrophin-deficient cardiomyopathy, including membrane instability, calcium dysregulation, mitochondrial dysfunction, and fibrosis. The role of inflammatory responses in disease progression is also discussed. In addition, we evaluate current and emerging therapeutic strategies, including gene therapy, pharmacological interventions, and regenerative medicine approaches, and highlight recent preclinical and clinical trial data. Finally, we explore future directions in precision medicine, novel biomarkers for early detection, and combination treatment regimens, to provide a comprehensive resource for clinicians and researchers working in this challenging field.
2026-01-01 | P269: Test the grandfather! Incidental in-frame DMD deletions in three asymptomatic families
The DMD gene encodes dystrophin, a protein that protects the sarcolemma from stress induced by muscle contraction and regulates other sarcolemma proteins. DMD, the largest gene in the human genome, is particularly prone to exonic deletions or duplications, causing recessive X-linked dystrophinopathies. Frameshift deletions are typically seen with Duchenne muscular dystrophy (DMD) and in-frame deletions with Becker muscular dystrophy (BMD) or DMD-associated isolated dilated cardiomyopathy (DCM). DMD in males presents in early childhood with progressive proximal muscle weakness, wheelchair dependence by early teens, markedly elevated creatine kinase (CK), and a life expectancy of 20-30 years.
2025-05-31 | Unraveling the spatial landscape of Dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies
Abstract Dystrophinopathies are caused by pathogenic variants in the DMD gene resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD), are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used spatial transcriptomics to profile skeletal muscle biopsies of BMD, DMD patients and healthy controls ( N = 4 per group). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using single-nuclei RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitor cells (FAPs) in areas of active pathology. Using expression data of ligand receptor pairs, we highlight cell-cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to become fat. Significance statement This study investigates the cellular and molecular changes that occur in muscles affected by Becker and Duchenne muscular dystrophy (BMD and DMD). These diseases are caused by mutations in the DMD gene, leading to muscle degeneration and the replacement of muscle tissue with fibrotic and fatty tissue causative for an early death. By using spatial transcriptomics, the researchers analyzed muscle biopsies from BMD, DMD patients, and healthy controls. They identified specific genes and cell types, such as fibroadipogenic progenitor cells, that are involved in disease progression. The study also revealed how different cells communicate with each other to drive muscle degeneration and fat accumulation. These findings provide new insights into the mechanisms of disease and potential targets for future therapies.
oligonucleotides
2026-05-20 | Progressive Duchenne/Becker muscular dystrophy, preclinical stage, deletion of exons 45-55 of the DMD gene in the hemizygous state: a clinical case from practice
Background. Duchenne/Becker progressive muscular dystrophy is an X-linked recessive disease caused by mutations in the DMD gene encoding the dystrophin protein. Deletions of exons 45-55 often correspond to the principle of preserving the reading frame, being associated with the Duchenne/Becker muscular dystrophy phenotype. Objective. To present a clinical case of the presymptomatic diagnosis of progressive Duchenne/Becker muscular dystrophy in an early-age patient with deletion of exons 45-55 of the DMD gene, analyze diagnostic markers and justify a strategy for dynamic follow-up. Materials and methods. A retrospective analysis of medical documentation with clinical, laboratory and instrumental methods was performed. In order to form a theoretical base, data was searched and systematized from scientific electronic libraries (CyberLeninka, eLibrary, PubMed, Google Academy) on progressive Duchenne/Becker muscular dystrophy (preclinical phase) and deletion of exons 45-55 of the DMD gene. The review includes literature reviews, scientific publications, and the results of clinical trials on the topic. Conclusion. A clinical case of diagnosis of progressive Duchenne/Becker muscular dystrophy in a 1-year-old male patient with isolated hyperfermentemia (ALT – 120 U/l, AST – 107.1 U/L) and a significant increase in creatine phosphokinase (4817.1 U/L) is described. Conducted: biochemical examination (creatine phosphokinase, lactate dehydrogenase, creatine phosphokinase-MV), instrumental diagnostics, including electrocardiography, ultrasound examination of the heart and abdominal cavity), molecular genetic analysis. The molecular genetic analysis method verified the hemizygous deletion of exons 45-55 of the DMD gene. The diagnosis of progressive Duchenne/Becker muscular dystrophy was established at the preclinical stage, despite the absence of manifest neurological symptoms. The case demonstrates the critical role of determining of creatine phosphokinase as a screening marker and the need for an integrated approach for early diagnosis. The detection of in-frame deletion creates prerequisites for the potential use of exon-skipping therapy.
2026-03-15 | Vaccination in Pediatric Hereditary and Genetic Neuromuscular disorders: Current Evidence-Based Recommendations
Hereditary and genetic neuromuscular diseases include Duchenne and Becker Muscular Dystrophies (DMD and BMD), Spinal Muscular Atrophy (SMA), Charcot–Marie–Tooth disease (CMT), Congenital Myopathies (CM), Limb-Girdle Muscular Dystrophies (LGMD), Myotonic Dystrophy (DM1 and DM2), and other less common muscular dystrophies. In the last decade, management approaches have witnessed a paradigm shift towards potentially curative targeted, disease-modifying therapies. This narrative review collates information up to December 2025, outlines the clinico-epidemiological profile, recent therapeutic developments, and summarizes current recommendations relevant to pediatric immunization, with level and grade of evidence. For DMD, newer therapeutic modalities include Exon skipping Antisense oligonucleotides (ASO) Eteplirsen, Golodirsen, Viltolarsen, and Casimersen, orally administered small molecule compound Ataluren, Adeno-associated virus-(AAV) mediated gene therapy Delandistrogene moxeparvovec, orally administered histone deacetylase inhibitor Givinostat, dissociative corticosteroid drug Vamorolone; and for SMA, ASO Nusinersen, AAV9 vector gene therapy Onasemnogene abeparvovec, and orally deliverable small molecule SMN2 RNA splicing modifier Risdiplam. Unlike DMD, where corticosteroids are the primary pharmacological treatment, the primary treatments for SMA are specific disease-modifying therapies. Corticosteroids and other immunosuppressants are used concomitantly with several disease modifying therapies. Only prednisone equivalent doses of ≥2 mg/kg body weight or ≥20 mg per day for weight >10 kg when administered for ≥14 consecutive days, are considered sufficiently immunosuppressive by the US Centers for Disease Control and Prevention (CDC) guidelines. In contrast, the Australian guidelines also consider both, a dose of <2 mg/kg per day for ≥14 days and ≥2 mg/kg per day for <14 days, to be immunosuppressive to preclude live vaccine administration during corticosteroid therapy. When indicated, gene therapy combined with corticosteroid therapy should be initiated a minimum 2-weeks after BCG vaccine administration. Live vaccine administration is recommended at least 4 weeks before or after administration of gene therapy with concomitant high dose corticosteroids. During gene therapy, all live vaccines are contraindicated, but not killed vaccines. Meningococcal conjugate vaccines are specifically recommended for patients with SMA, especially if thrombotic microangiopathy develops and eculizumab is used for treatment. The optimal (most immunogenic with least adverse events) route of vaccine administration in patients with neuromuscular disorders, despite significant muscle atrophy and muscle replacement by fat, is intramuscular, due to largely preserved vascularity.
2026-01-08 | A new dystrophin-deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions
Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most-frequent single-exon deletion in patients diagnosed with DMD. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function, and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly of exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.
2025-11-01 | Genotype-Phenotype Correlation in a Cohort of Egyptian Patients with Dystrophinopathies
Abstract Background Dystrophinopathies are a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD- associated dilated cardiomyopathy (DCM). They are classified according to primary muscle affection, where DMD/ BMD occur when skeletal muscle is affected and DMD - related DCM when heart is primarily affected. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X- linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Objective To describe demographic and clinical data in relation to different genetic mutations and to correlate between phenotypic and genotypic differences in a cohort of Egyptian patients with dystrophinopathies. Methods This Descriptive observational study was conducted in Ain Shams University muscle clinic research committee over 6 months. Our study was conducted upon 109 patients with dystrophinopathies encompassing Duchenne and Becker muscular dystrophies confirmed by Multiplex ligation probe amplification (MLPA) for dystrophin gene. The subjects were randomly chosen from neuromuscular clinic in Ain shams university hospitals. Results In our study, genotype -phenotype correlations were performed showing that most patients with DMD phenotype follow the reading frame rule except for patient with in frame deletion affecting exons 31-41 result still in DMD phenotype. Other exceptions to the reading frame rule was also identified, where two patients with BMD phenotype had out frame deletions of exons 3-7 and exons 46-48. Conclusion Assessing the genotype–phenotype relationship in patients with dystrophinopathies has been supported by data from clinical studies, which might more directly indicate the merits of potential exon-skipping therapies. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments still do not cure the disease only ameliorate the disease severity. Our study revealed that genotype–phenotype correlations of enrolled subjects comply with the reading frame rule in most patients with DMD and BMD phenotype except for some exceptions. In addition to that, we identified cases with specific deletion mutations and nonsense mutations amenable for exon skipping therapies as exon 45 skipping, exon 51 skipping and ataluren therapy respectively.
2025-10-01 | Reduced Muscle Force in Dystrophic DMDΔ52 Pigs Is Incompletely Restored by Systemic Transcript Reframing (DMDΔ51–52)
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to dystrophin deficiency and progressive degeneration of skeletal and cardiac muscles. Pigs lacking DMD exon 52 (DMDΔ52) are a clinically severe model for DMD, mimicking molecular, functional and pathological hallmarks of the human disease. Dystrophin expression can be restored by additionally deleting exon 51 (DMDΔ51-52), which reframes DMD transcripts and alleviates pathological alterations. DMDΔ51-52 pigs model Becker muscular dystrophy (BMD), a milder and slower-progressing form of muscle degeneration. The Aurora Swine Isometric Footplate Test Apparatus was used to quantify functional parameters of the hind limb dorsiflexor muscle group of 3.5-month-old DMD pigs (n = 5), BMD pigs (n = 3) and wild-type (WT) littermate controls (n = 3). In addition, histopathological and proteomic studies of the functionally tested muscles were performed. After twitch stimulation, DMD muscle achieved 62.4% (p < 0.05) and BMD muscle 67.1% (p < 0.05) of the absolute peak force of WT muscle, indicating partial but not complete restoration of muscle force by DMDΔ51-52 transcript reframing. After normalization to the cube root of body mass, the values were 70.9% for DMD muscle (p = 0.05) and 65.8% for BMD muscle (p < 0.05). DMD muscle showed a reduced rate of contraction (p < 0.01); the rate of relaxation was decreased in both DMD (p < 0.01) and BMD (p < 0.05) compared with WT muscle. After tetanic stimulation, DMD muscle reached 54.7% (p < 0.001) and BMD muscle 80.4% (p = 0.08) of WT muscle force. Normalized values were 62.7% (DMD; p < 0.01) and 79.3% (BMD; p = 0.08). The rate of contraction was reduced in both DMD (p < 0.001) and BMD muscle (p < 0.01), whereas the return to the resting state was prolonged (p < 0.001) only in DMD vs. WT muscle. Histopathology and proteomics revealed no significant differences between BMD and WT muscles, whereas severe alterations were observed in DMD pigs. Our study pioneers the quantitative assessment of skeletal muscle function in dystrophic pigs. It demonstrates that systemic exon 51 skipping in DMD caused by loss of DMD exon 52 partially restores muscle function but does not achieve WT levels. These findings highlight the value of dynamic muscle force measurements as a sensitive tool to evaluate the efficacy of therapeutic interventions in the porcine DMD model.
proteins
2026-05-01 | Engineered antibody fusion proteins increase plasma membrane repair to treat muscle diseases
Plasma membrane repair is a highly conserved process that muscle cells use to maintain health under mechanical stress from physiological levels of muscle contraction. Defective sarcolemma repair can cause or exacerbate cardiovascular and muscle diseases, including Duchenne/Becker muscular dystrophy and limb-girdle muscular dystrophies. The tripartite motif family protein 72 (TRIM72), also called mitsugumin 53 (MG53), is essential for membrane repair by facilitating vesicle fusion at injury sites while binding the phospholipid phosphatidylserine (PS). Our laboratory and others have shown that treatment with recombinant TRIM72 protein (rhTRIM72) ameliorates muscle disease pathology in preclinical models. However, the therapeutic potential of rhTRIM72 in muscle diseases was limited by off-target effects on systemic metabolism, poor pharmacokinetics, and manufacturing challenges. To address these issues, we created improved therapeutic proteins by fusing the fragment crystallizable (Fc) domain from the human IgG1 protein to a panel of TRIM72 truncations. We hypothesized that this approach would increase protein serum half-life through endogenous antibody recycling machinery, simplify manufacturing using existing biologic drug purification methods, and decrease off-target effects by truncating TRIM72. Multiple TRIM72/Fc-fusion proteins display effective PS binding activity in biochemical pulldown experiments. Laser confocal microscopy ablation and dye exclusion assays in myoblast cells revealed that TRIM72/Fc-fusion proteins improved plasma membrane repair upon intracellular overexpression or exogenous application. These experiments found that one of the fusion proteins we call MyoSPRY, comprised of the Fc fused to the SPRY domain of TRIM72, could increase membrane repair. Exogenous treatment with MyoSPRY and other Fc-SPRY proteins improved membrane repair in live muscle tissue isolated from a Duchenne muscular dystrophy (DMD) mouse model. Subcutaneous injection experiments show that Fc-fusion proteins exhibit extended half-lives in vivo and protect muscle against acute eccentric contraction injury-induced force decrement in a mouse model of DMD. Together, these results indicate that our novel Fc-fusion proteins address barriers impeding the clinical development of rhTRIM72 and represent a possible therapeutic approach for diseases driven by altered membrane integrity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2025-06-07 | Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS
Abstract Background Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance. Methods Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time. Results Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle. Conclusions Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.
2024-05-01 | Enhancing Sarcolemmal Membrane Repair Using a Novel Protein Therapeutic Approach can Improve Membrane Integrity in Duchenne Muscular Dystrophy Cells and Mouse Models
Duchenne Muscular Dystrophy (DMD) is a fatal neuromuscular disease involving progressive cardiac and skeletal myocyte cell death and subsequent muscle degeneration. DMD and Becker muscular dystrophy (BMD) result from mutations in the dystrophin gene that compromise the structural integrity of the sarcolemma. While there has been important recent progress in the treatment of DMD, the currently available therapeutics have significant limitations. Thus, novel therapies that address the compromised sarcolemmal membrane integrity are an unmet medical need. Tripartite motif protein 72, or mitsugumin 53 (TRIM72/MG53), facilitates the sarcolemma repair response after disruption of the membrane. Loss of TRIM72/MG53 function in mice leads to a progressive myopathy. Exogenous delivery of recombinant human MG53 protein (rhMG53) can increase sarcolemmal membrane repair in many different cell types and ameliorate pathology in models of DMD and multiple limb girdle muscular dystrophies. Despite the promise of rhMG53 as a therapeutic invention the development of this protein to treat DMD has been complicated by findings showing that high levels of the protein correlate with metabolic dysfunction in animal models and some human patients. Deletion analysis of the major domains of the rhMG53 protein allowed us to design an improved version of rhMG53 called MyoTRIM. MyoTRIM contains amino acid replacements to eliminate metabolic effects and improve solubility while maintaining membrane repair effects. One set of modifications inactivate the E3 ligase activity of the protein, which revealed this function is dispensable for subcellular localization of the protein. TRIM72/MG53 is reported to mediate this effect by binding phosphatidylserine (PS) at membrane injury sites, so we demonstrate that MyoTRIM can bind PS-coated beads to illustrate that carboxy-terminal domains are required for effcient PS binding rather than the E3 ligase function. External application of MyoTRIM can increase membrane repair capacity in a variety of cell-based assays using DMD and BMD patient myoblasts and myotubes. We also establish that MyoTRIM can increase membrane repair and prevent eccentric contraction induced injury in a dystrophin deficient mouse model. Taken together, these results provide mechanistic insight into rhMG53 function and indicate that MyoTRIM can recapitulate the therapeutic effects on sarcolemmal membrane repair while eliminating E3 ligase activity and associated side effects. This work was supported by the Offce of the Assistant Secretary of Defense for Health Affairs through the Duchenne Muscular Dystrophy Research Program (DMDRP) under Translational Research Award HT9425-23-1-0940. The opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2019-08-06 | Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
Abstract Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 – a locally acting, follistatin-based fusion protein – as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, activin A, activin B and growth differentiation factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness.
2015-05-05 | MicroRNAs modulated by local mIGF-1 expression in mdx dystrophic mice
Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and mir-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle.
small molecules
2026-07-01 | Human Disposition, Metabolism, and Excretion of Sevasemten (EDG‐5506), a Selective Modulator of Fast Myosin in Healthy Volunteers
Abstract Sevasemten (EDG‐5506) is a novel, orally bioavailable, investigational small molecule designed to selectively modulate type II fast skeletal myosin with the goal of protecting dystrophic muscle from contraction‐induced injury. Sevasemten is in clinical development for the treatment of Becker and Duchenne muscular dystrophy. In the current Phase 1 study (NCT05730842), eight participants were dosed with a 20 mg single oral suspension dose of sevasemten containing approximately 500 µCi [ 14 C] sevasemten. Blood and urine samples were collected to evaluate the pharmacokinetics (PK), oral absorption, metabolism, and excretion (AME) of sevasemten and its metabolites. A second cohort of seven participants received a single 20 mg oral dose of sevasemten, followed 2 h later by a single dose of [ 14 C] sevasemten administered as a single intravenous (IV) bolus with approximately 1 µCi [ 14 C] sevasemten to determine absolute bioavailability. Sevasemten was excreted primarily in urine (52.1%) subsequent to CYP3A‐mediated metabolism, and 8.89% was eliminated in the feces, for a total of 61.0% recovered over 840 h post‐dose. Most of the recoverable radioactivity was excreted by 576 h (24 days). However, sevasemten total radioactivity in plasma and whole blood was characterized by a very slow elimination phase of 16.1–20.6 days; total recovery of radioactivity was not achieved. Sevasemten was well tolerated, with no serious adverse events or adverse events leading to study discontinuation. Sevasemten has favorable PK properties for once daily administration and continues to be investigated for the treatment of Becker and Duchenne muscular dystrophies.
2026-06-17 | Effects of sevasemten (EDG-5506) on safety, biomarkers, and functional measures in adults with Becker muscular dystrophy: results of a phase 1b, open-label study.
Sevasemten (EDG-5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fibre contraction by inhibiting fast myosin ATPase. In animal models of Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), sevasemten reduced the muscle contraction injury that leads to inflammation, fibrosis and muscle loss without affecting function. The aim of this study was to evaluate the long-term safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics of sevasemten in adult participants with BMD who had already experienced a decline in function and would be anticipated to continue to decline based on natural history. This open-label, dose escalation, phase 1 b study (NCT05160415) was conducted at a single site and enrolled ambulatory adults with BMD aged 18-55 years; the study is completed. Eligible participants received 10 mg of sevasemten once daily (QD) for 8 weeks, followed by 15 mg QD for 4 months, 20 mg QD for 9 months, and 10 mg QD for 9 months. The primary objective was to assess the safety and tolerability of sevasemten in adults with BMD; endpoints included adverse events (AEs), PK, change from baseline in circulating biomarkers of muscle injury, as well as physical function measures. The study enrolled 12 adults with BMD. Sevasemten was well tolerated; all AEs were mild or moderate in severity and there were no serious AEs or AEs leading to discontinuation. Treatment with sevasemten was associated with reductions in circulating biomarkers of muscle injury that were evident within 4 weeks and sustained for up to 24 months. Physical function, as assessed by North Star Ambulatory Assessment (NSAA), was stable over 24 months. Sevasemten treatment for up to 24 months in adults with BMD was well tolerated and associated with durable reductions in muscle injury biomarkers, consistent with preclinical studies and near maximal with the 10 mg dose, as well as functional stabilisation. Further clinical development is ongoing. Edgewise Therapeutics, Inc.
2026-05-20 | Heart failure guideline-directed medical therapy in young adults with dystrophin-related cardiomyopathy: the HOPE-MD registry
BACKGROUND: Duchenne (DMD) and Becker (BMD) muscular dystrophies often progress to dilated cardiomyopathy and heart failure with reduced ejection fraction (HFrEF), a major cause of death in affected patients. Although guideline-directed medical therapy (GDMT) improves HFrEF outcomes, its real-world use in dystrophinopathies is poorly defined. We assessed GDMT utilization and optimization in the study population. METHODS: HOPE-MD is a European, multicentre, retrospective registry including adults with genetically confirmed DMD or BMD and left ventricular ejection fraction (LVEF) ≤40%. GDMT was defined as concurrent use of a renin-angiotensin system inhibitor (RASi), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter-2 inhibitor (SGLT2i). Doses were categorized as target (≥100%), intermediate (50-99%), or low (<50%). RESULTS: Among 274 patients (age, 28 years; LVEF, 35%; DMD, 80%), 44 (16%) received GDMT at baseline, with only one quarter at ≥50% of the target dose. Underutilization was greatest for MRAs (n=140, 51%) and SGLT2i (n=60, 22%), whereas RASi (n=246, 90%) and beta-blockers (n=235, 86%) were frequently prescribed. After 24 months (n=141), 40% received GDMT, and 22% received ≥50% of the target dose, primarily through MRA and SGLT2i initiation/uptitration. Contraindications accounted for only a small proportion of undertreatment. At a median follow-up of 2.2 (1.7-2.6) years, optimized GDMT was not associated with a statistically significant difference in the rates of death or HF hospitalization compared with low-dose or no GDMT (adjusted HR 0.70, 95% CI 0.28-1.74). CONCLUSIONS: GDMT use and dose escalation were suboptimal in European patients with DMD/BMD and HFrEF.
2026-02-09 | (Z)-Endoxifen as a Modulator of Utrophin Pathways in Duchenne Muscular Dystrophy: A Mechanistic and Transcriptomic Perspective
Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disorder caused by mutations in the dystrophin gene, leading to sarcolemmal instability, chronic calcium overload, mitochondrial dysfunction, inflammation, and fibrosis. These effects manifest clinically as muscle atrophy, loss of mobility, and respiratory and cardiac insufficiencies. Although gene-targeted approaches such as exon skipping and microdystrophin delivery have advanced, their applicability is restricted by genotype and adverse effects. Thus, reasonably safe, effective therapies remain a critical unmet need. (Z)‑endoxifen, the (Z)-isomer of endoxifen, is the principal active metabolite of tamoxifen, exhibiting higher potency in protein kinase C (PKC) inhibition than tamoxifen and regulating various protein activities differently than tamoxifen. This pharmacologic profile positions endoxifen to address multiple DMD pathomechanisms simultaneously. Recent literature supports the prior hypothesis that endoxifen exerts pleiotropic benefits in DMD. Transcriptomic and preclinical evidence shows that endoxifen may have superior effects to tamoxifen in reversing DMD signatures given available dosing regimens. Additionally, pathway level insights support endoxifen activation of myogenesis, oxidative phosphorylation, estrogen receptor beta (ERβ) activation, and inhibition of pro-inflammatory and epithelial-to-mesenchymal transition (EMT) pathways in DMD. These findings suggest (Z)‑endoxifen acts on utrophin-linked regulatory axes potentially contributing to functional compensation for dystrophin deficiency, providing justification for its development as a mutation-agnostic DMD therapeutic approach. Keywords: gene expression regulation, selective estrogen receptor modulators, skeletal muscle regeneration, pharmacologic action mechanism, Becker muscular dystrophy
2026-01-01 | Response to the Letter Regarding "If Becker Muscular Dystrophy Initially Manifests with Heart Disease and Rhabdomyolysis, Neurological Work-up is Imperative"
We thank Dr. Finsterer for his interest in our case report (1) and for responding to the questions and comments.The patient presented with only mildly elevated creatine kinase (CPK) levels, and both his leg press strength and hand grip strength were within the normal limits, although patients with Becker muscular dystrophy (BMD) typically exhibit skeletal muscle symptoms preceding myocardial dysfunction.Although the patient did not undergo a neurological examination at the time of rhabdomyolysis onset, mild skeletal muscle symptoms, such as mild muscle atrophy or diminished tendon reflexes, might have been detected, as Dr. Finsterer suggested.Dilated cardiomyopathy and left ventricular noncompaction (LVNC) have both been reported in patients with Duchenne muscular dystrophy and BMD (2, 3).In our case, the echocardiographic findings did not meet the criteria for LVNC and the explanted heart showed no prominent trabeculation or intertrabecular thrombus formation.The development of rhabdomyolysis remains necessary even after transplantation.Rhabdomyolysis has been reported to occur with immunosuppressive agents in patients who have undergone organ or bone marrow transplantation (4-7).Our patient received standard tacrolimus-based triple immunosuppression ( tacrolimus, mycophenolate mofetil, and prednisolone), and mycophenolate mofetil was switched to everolimus at 8 months post-transplant due to a cytomegalovirus infection and neutropenia.Currently, the CPK levels fluctuate between approximately 700 and 1,500 IU/L, and follow-up is being conducted with regular monitoring of the immunosuppressant blood concentrations to prevent the development of rhabdomyolysis.Read-through therapy has been used in patients with dys-trophy and nonsense mutations, primarily in Europe.However, because it has not yet been approved in Japan, this therapy was not used in our patient.Finally, antibodies against dystrophin are formed in the transplanted hearts of these patients (8).Although we did not measure the antibodies in this case, no recurrent rejection episodes or graft loss were observed.
gene therapies
2026-09-15 | Development of an AAV-Encoded Adenine Base Editor for Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a devastating X-linked disorder caused by out-of-frame mutations in the DMD gene, most commonly large deletions or duplications, as well as nonsense and splice site mutations, that result in the absence of functional dystrophin protein. These mutations lead to progressive skeletal and cardiac muscle failure. In particular, exon 52 of the DMD gene represents a mutational hotspot in DMD patients. Deletion of exon 52 ( DMD Δ52) disrupts the reading frame, leading to premature termination of translation. Here, we used a dual recombinant adeno-associated virus (rAAV) system employing an intein-mediated split strategy to deliver ABE8e using the PAM-less SpRY Cas9 nickase for adenine base editing of splice acceptor sites (SAS) in the dystrophin gene. Targeting the SAS of exon 51 or exon 53 in a DMD Δ52 background aims to induce exon skipping, thereby restoring the open reading frame, in effect converting the severe DMD phenotype into a milder Becker muscular dystrophy (BMD)-like phenotype. We systematically screened sgRNAs in porcine kidney fibroblasts and human embryonic kidney cells (HEK293T), identifying a guide RNA targeting the SAS of exon 53 as the most effective candidate with high on-target editing efficacies and minimal bystander editing. In human DMDΔ52 iPSC-derived cardiomyocytes cultivated as 2D monolayers, high editing efficiencies were achieved with the optimized 1:2 ratio of N-Terminus to C-Terminus. Functional assessment in 3D engineered heart patches revealed a trend toward normalization of the arrhythmic DMD phenotype with an increase in the effective refractory period (ERP) and a reduction in arrhythmic load compared with untreated DMD patches, despite lower editing efficacy in the 3D setting. These findings suggest that even modest levels of base editing-mediated exon skipping may ameliorate the DMD cardiac phenotype toward a BMD-like state, supporting the translational potential of this dual rAAV base editing approach for DMD cardiomyopathy.
2026-06-05 | Gene editing restores full-length dystrophin and affects iron homeostasis in hiPSC-derived cardiomyocytes from Becker Muscular Dystrophy patients
Becker Muscular Dystrophy (BMD) is caused by in-frame mutations in the DMD gene, leading to the production of internally truncated but partially functional dystrophin. Although cardiac involvement is a major contributor to disease burden in BMD, the cellular mechanisms driving cardiomyopathy remain incompletely understood. While emerging evidence suggests that iron imbalance may contribute to oxidative stress and mitochondrial dysfunction in muscular dystrophies, its role in BMD-associated cardiomyopathy has not been defined. Building on our previous findings of dysregulated iron homeostasis in dystrophin-deficient cardiomyocytes from Duchenne muscular dystrophy (DMD), we investigated whether similar alterations are present in BMD using patient-specific and genome-corrected hiPSC-CM models. HiPSC lines derived from two BMD patients and their CRISPR/Cas9-corrected isogenic controls displayed normal karyotype, pluripotency, and efficient differentiation into cardiomyocytes (hiPSC-CMs). BMD hiPSC-CMs showed elevated ROS levels and decreased cytoplasmic and mitochondrial labile iron pools, accompanied by reduced expression of mitoNEET ( CISD1 ), a regulator of mitochondrial iron handling. We also detected changes in the expression of genes involved in iron storage ( FTH1 ), uptake ( TFRC ), and export ( SLC40A1 ), suggesting a dysregulation of iron trafficking. Importantly, correction of DMD mutation by CRISPR/Cas9 gene editing reversed the effects observed in BMD cardiomyocytes. These results extend our previous observations in DMD to BMD cardiomyocytes and suggest that full-length dystrophin is essential for maintaining cardiac iron homeostasis.
2026-03-16 | Molecular Mechanisms and Therapeutic Strategies in Heart Failure Due to Dystrophin Deficiency: A Comprehensive Review
Dystrophin deficiency is the core pathological feature of Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD). Indeed, a deficiency in dystrophin results in the progressive degeneration of skeletal muscle and severely compromises the structure and function of cardiomyocytes, eventually leading to dilated cardiomyopathy and heart failure. Thus, this review provides an in-depth analysis of the molecular mechanisms underlying dystrophin-deficient cardiomyopathy, including membrane instability, calcium dysregulation, mitochondrial dysfunction, and fibrosis. The role of inflammatory responses in disease progression is also discussed. In addition, we evaluate current and emerging therapeutic strategies, including gene therapy, pharmacological interventions, and regenerative medicine approaches, and highlight recent preclinical and clinical trial data. Finally, we explore future directions in precision medicine, novel biomarkers for early detection, and combination treatment regimens, to provide a comprehensive resource for clinicians and researchers working in this challenging field.
2026-01-01 | P269: Test the grandfather! Incidental in-frame DMD deletions in three asymptomatic families
The DMD gene encodes dystrophin, a protein that protects the sarcolemma from stress induced by muscle contraction and regulates other sarcolemma proteins. DMD, the largest gene in the human genome, is particularly prone to exonic deletions or duplications, causing recessive X-linked dystrophinopathies. Frameshift deletions are typically seen with Duchenne muscular dystrophy (DMD) and in-frame deletions with Becker muscular dystrophy (BMD) or DMD-associated isolated dilated cardiomyopathy (DCM). DMD in males presents in early childhood with progressive proximal muscle weakness, wheelchair dependence by early teens, markedly elevated creatine kinase (CK), and a life expectancy of 20-30 years.
2025-05-31 | Unraveling the spatial landscape of Dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies
Abstract Dystrophinopathies are caused by pathogenic variants in the DMD gene resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD), are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used spatial transcriptomics to profile skeletal muscle biopsies of BMD, DMD patients and healthy controls ( N = 4 per group). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using single-nuclei RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitor cells (FAPs) in areas of active pathology. Using expression data of ligand receptor pairs, we highlight cell-cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to become fat. Significance statement This study investigates the cellular and molecular changes that occur in muscles affected by Becker and Duchenne muscular dystrophy (BMD and DMD). These diseases are caused by mutations in the DMD gene, leading to muscle degeneration and the replacement of muscle tissue with fibrotic and fatty tissue causative for an early death. By using spatial transcriptomics, the researchers analyzed muscle biopsies from BMD, DMD patients, and healthy controls. They identified specific genes and cell types, such as fibroadipogenic progenitor cells, that are involved in disease progression. The study also revealed how different cells communicate with each other to drive muscle degeneration and fat accumulation. These findings provide new insights into the mechanisms of disease and potential targets for future therapies.
oligonucleotides
2026-05-20 | Progressive Duchenne/Becker muscular dystrophy, preclinical stage, deletion of exons 45-55 of the DMD gene in the hemizygous state: a clinical case from practice
Background. Duchenne/Becker progressive muscular dystrophy is an X-linked recessive disease caused by mutations in the DMD gene encoding the dystrophin protein. Deletions of exons 45-55 often correspond to the principle of preserving the reading frame, being associated with the Duchenne/Becker muscular dystrophy phenotype. Objective. To present a clinical case of the presymptomatic diagnosis of progressive Duchenne/Becker muscular dystrophy in an early-age patient with deletion of exons 45-55 of the DMD gene, analyze diagnostic markers and justify a strategy for dynamic follow-up. Materials and methods. A retrospective analysis of medical documentation with clinical, laboratory and instrumental methods was performed. In order to form a theoretical base, data was searched and systematized from scientific electronic libraries (CyberLeninka, eLibrary, PubMed, Google Academy) on progressive Duchenne/Becker muscular dystrophy (preclinical phase) and deletion of exons 45-55 of the DMD gene. The review includes literature reviews, scientific publications, and the results of clinical trials on the topic. Conclusion. A clinical case of diagnosis of progressive Duchenne/Becker muscular dystrophy in a 1-year-old male patient with isolated hyperfermentemia (ALT – 120 U/l, AST – 107.1 U/L) and a significant increase in creatine phosphokinase (4817.1 U/L) is described. Conducted: biochemical examination (creatine phosphokinase, lactate dehydrogenase, creatine phosphokinase-MV), instrumental diagnostics, including electrocardiography, ultrasound examination of the heart and abdominal cavity), molecular genetic analysis. The molecular genetic analysis method verified the hemizygous deletion of exons 45-55 of the DMD gene. The diagnosis of progressive Duchenne/Becker muscular dystrophy was established at the preclinical stage, despite the absence of manifest neurological symptoms. The case demonstrates the critical role of determining of creatine phosphokinase as a screening marker and the need for an integrated approach for early diagnosis. The detection of in-frame deletion creates prerequisites for the potential use of exon-skipping therapy.
2026-03-15 | Vaccination in Pediatric Hereditary and Genetic Neuromuscular disorders: Current Evidence-Based Recommendations
Hereditary and genetic neuromuscular diseases include Duchenne and Becker Muscular Dystrophies (DMD and BMD), Spinal Muscular Atrophy (SMA), Charcot–Marie–Tooth disease (CMT), Congenital Myopathies (CM), Limb-Girdle Muscular Dystrophies (LGMD), Myotonic Dystrophy (DM1 and DM2), and other less common muscular dystrophies. In the last decade, management approaches have witnessed a paradigm shift towards potentially curative targeted, disease-modifying therapies. This narrative review collates information up to December 2025, outlines the clinico-epidemiological profile, recent therapeutic developments, and summarizes current recommendations relevant to pediatric immunization, with level and grade of evidence. For DMD, newer therapeutic modalities include Exon skipping Antisense oligonucleotides (ASO) Eteplirsen, Golodirsen, Viltolarsen, and Casimersen, orally administered small molecule compound Ataluren, Adeno-associated virus-(AAV) mediated gene therapy Delandistrogene moxeparvovec, orally administered histone deacetylase inhibitor Givinostat, dissociative corticosteroid drug Vamorolone; and for SMA, ASO Nusinersen, AAV9 vector gene therapy Onasemnogene abeparvovec, and orally deliverable small molecule SMN2 RNA splicing modifier Risdiplam. Unlike DMD, where corticosteroids are the primary pharmacological treatment, the primary treatments for SMA are specific disease-modifying therapies. Corticosteroids and other immunosuppressants are used concomitantly with several disease modifying therapies. Only prednisone equivalent doses of ≥2 mg/kg body weight or ≥20 mg per day for weight >10 kg when administered for ≥14 consecutive days, are considered sufficiently immunosuppressive by the US Centers for Disease Control and Prevention (CDC) guidelines. In contrast, the Australian guidelines also consider both, a dose of <2 mg/kg per day for ≥14 days and ≥2 mg/kg per day for <14 days, to be immunosuppressive to preclude live vaccine administration during corticosteroid therapy. When indicated, gene therapy combined with corticosteroid therapy should be initiated a minimum 2-weeks after BCG vaccine administration. Live vaccine administration is recommended at least 4 weeks before or after administration of gene therapy with concomitant high dose corticosteroids. During gene therapy, all live vaccines are contraindicated, but not killed vaccines. Meningococcal conjugate vaccines are specifically recommended for patients with SMA, especially if thrombotic microangiopathy develops and eculizumab is used for treatment. The optimal (most immunogenic with least adverse events) route of vaccine administration in patients with neuromuscular disorders, despite significant muscle atrophy and muscle replacement by fat, is intramuscular, due to largely preserved vascularity.
2026-01-08 | A new dystrophin-deficient rat model mirroring exon skipping in patients with DMD exon 45 deletions
Pathogenic variants in the dystrophin (DMD) gene cause muscle-wasting disorders ranging from the milder Becker muscular dystrophy (BMD) to the more severe Duchenne muscular dystrophy (DMD). Exon 45 deletion is the most-frequent single-exon deletion in patients diagnosed with DMD. Here, we generated a novel rat model with an exon 45 deletion using CRISPR/Cas9. The DmdΔ45 rat recapitulate key features of DMD, including progressive skeletal muscle degeneration, impaired muscle and cardiac function, and cognitive deficits. Transcriptomics analyses revealed gene expression patterns consistent with dystrophin deficiency. In skeletal muscle, we observed a transition from early stress responses and regeneration to chronic inflammation, fibrosis and metabolic dysfunction. Cardiac profiles similarly progressed from early inflammatory responses to fibrotic remodelling and metabolic impairment. Notably, DmdΔ45 rats displayed a milder phenotype than other DMD rat models. This attenuation is likely due to spontaneous exon skipping, particularly of exon 44, which partially restores the reading frame and increases revertant dystrophin-positive fibres with age. Downregulation of spliceosome-related genes suggests a potential mechanism for this exon skipping. Overall, this model provides valuable insights into phenotypic variability and therapeutic exon-skipping strategies.
2025-11-01 | Genotype-Phenotype Correlation in a Cohort of Egyptian Patients with Dystrophinopathies
Abstract Background Dystrophinopathies are a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD- associated dilated cardiomyopathy (DCM). They are classified according to primary muscle affection, where DMD/ BMD occur when skeletal muscle is affected and DMD - related DCM when heart is primarily affected. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X- linked dystrophin gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Objective To describe demographic and clinical data in relation to different genetic mutations and to correlate between phenotypic and genotypic differences in a cohort of Egyptian patients with dystrophinopathies. Methods This Descriptive observational study was conducted in Ain Shams University muscle clinic research committee over 6 months. Our study was conducted upon 109 patients with dystrophinopathies encompassing Duchenne and Becker muscular dystrophies confirmed by Multiplex ligation probe amplification (MLPA) for dystrophin gene. The subjects were randomly chosen from neuromuscular clinic in Ain shams university hospitals. Results In our study, genotype -phenotype correlations were performed showing that most patients with DMD phenotype follow the reading frame rule except for patient with in frame deletion affecting exons 31-41 result still in DMD phenotype. Other exceptions to the reading frame rule was also identified, where two patients with BMD phenotype had out frame deletions of exons 3-7 and exons 46-48. Conclusion Assessing the genotype–phenotype relationship in patients with dystrophinopathies has been supported by data from clinical studies, which might more directly indicate the merits of potential exon-skipping therapies. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments still do not cure the disease only ameliorate the disease severity. Our study revealed that genotype–phenotype correlations of enrolled subjects comply with the reading frame rule in most patients with DMD and BMD phenotype except for some exceptions. In addition to that, we identified cases with specific deletion mutations and nonsense mutations amenable for exon skipping therapies as exon 45 skipping, exon 51 skipping and ataluren therapy respectively.
2025-10-01 | Reduced Muscle Force in Dystrophic DMDΔ52 Pigs Is Incompletely Restored by Systemic Transcript Reframing (DMDΔ51–52)
Duchenne muscular dystrophy (DMD) is a fatal X-linked disease caused by mutations in the DMD gene, leading to dystrophin deficiency and progressive degeneration of skeletal and cardiac muscles. Pigs lacking DMD exon 52 (DMDΔ52) are a clinically severe model for DMD, mimicking molecular, functional and pathological hallmarks of the human disease. Dystrophin expression can be restored by additionally deleting exon 51 (DMDΔ51-52), which reframes DMD transcripts and alleviates pathological alterations. DMDΔ51-52 pigs model Becker muscular dystrophy (BMD), a milder and slower-progressing form of muscle degeneration. The Aurora Swine Isometric Footplate Test Apparatus was used to quantify functional parameters of the hind limb dorsiflexor muscle group of 3.5-month-old DMD pigs (n = 5), BMD pigs (n = 3) and wild-type (WT) littermate controls (n = 3). In addition, histopathological and proteomic studies of the functionally tested muscles were performed. After twitch stimulation, DMD muscle achieved 62.4% (p < 0.05) and BMD muscle 67.1% (p < 0.05) of the absolute peak force of WT muscle, indicating partial but not complete restoration of muscle force by DMDΔ51-52 transcript reframing. After normalization to the cube root of body mass, the values were 70.9% for DMD muscle (p = 0.05) and 65.8% for BMD muscle (p < 0.05). DMD muscle showed a reduced rate of contraction (p < 0.01); the rate of relaxation was decreased in both DMD (p < 0.01) and BMD (p < 0.05) compared with WT muscle. After tetanic stimulation, DMD muscle reached 54.7% (p < 0.001) and BMD muscle 80.4% (p = 0.08) of WT muscle force. Normalized values were 62.7% (DMD; p < 0.01) and 79.3% (BMD; p = 0.08). The rate of contraction was reduced in both DMD (p < 0.001) and BMD muscle (p < 0.01), whereas the return to the resting state was prolonged (p < 0.001) only in DMD vs. WT muscle. Histopathology and proteomics revealed no significant differences between BMD and WT muscles, whereas severe alterations were observed in DMD pigs. Our study pioneers the quantitative assessment of skeletal muscle function in dystrophic pigs. It demonstrates that systemic exon 51 skipping in DMD caused by loss of DMD exon 52 partially restores muscle function but does not achieve WT levels. These findings highlight the value of dynamic muscle force measurements as a sensitive tool to evaluate the efficacy of therapeutic interventions in the porcine DMD model.
proteins
2026-05-01 | Engineered antibody fusion proteins increase plasma membrane repair to treat muscle diseases
Plasma membrane repair is a highly conserved process that muscle cells use to maintain health under mechanical stress from physiological levels of muscle contraction. Defective sarcolemma repair can cause or exacerbate cardiovascular and muscle diseases, including Duchenne/Becker muscular dystrophy and limb-girdle muscular dystrophies. The tripartite motif family protein 72 (TRIM72), also called mitsugumin 53 (MG53), is essential for membrane repair by facilitating vesicle fusion at injury sites while binding the phospholipid phosphatidylserine (PS). Our laboratory and others have shown that treatment with recombinant TRIM72 protein (rhTRIM72) ameliorates muscle disease pathology in preclinical models. However, the therapeutic potential of rhTRIM72 in muscle diseases was limited by off-target effects on systemic metabolism, poor pharmacokinetics, and manufacturing challenges. To address these issues, we created improved therapeutic proteins by fusing the fragment crystallizable (Fc) domain from the human IgG1 protein to a panel of TRIM72 truncations. We hypothesized that this approach would increase protein serum half-life through endogenous antibody recycling machinery, simplify manufacturing using existing biologic drug purification methods, and decrease off-target effects by truncating TRIM72. Multiple TRIM72/Fc-fusion proteins display effective PS binding activity in biochemical pulldown experiments. Laser confocal microscopy ablation and dye exclusion assays in myoblast cells revealed that TRIM72/Fc-fusion proteins improved plasma membrane repair upon intracellular overexpression or exogenous application. These experiments found that one of the fusion proteins we call MyoSPRY, comprised of the Fc fused to the SPRY domain of TRIM72, could increase membrane repair. Exogenous treatment with MyoSPRY and other Fc-SPRY proteins improved membrane repair in live muscle tissue isolated from a Duchenne muscular dystrophy (DMD) mouse model. Subcutaneous injection experiments show that Fc-fusion proteins exhibit extended half-lives in vivo and protect muscle against acute eccentric contraction injury-induced force decrement in a mouse model of DMD. Together, these results indicate that our novel Fc-fusion proteins address barriers impeding the clinical development of rhTRIM72 and represent a possible therapeutic approach for diseases driven by altered membrane integrity. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.
2025-06-07 | Contrasting Becker and Duchenne muscular dystrophy serum biomarker candidates by using data independent acquisition LC-MS/MS
Abstract Background Becker muscular dystrophy (BMD) is a rare and heterogeneous form of dystrophinopathy caused by expression of altered dystrophin proteins, as a consequence of in-frame genetic mutations. The majority of the BMD biomarker studies employ targeted approaches and focus on translating findings from Duchenne Muscular Dystrophy (DMD), a more severe disease form with clinical similarities but caused by out-of-frame mutations in the dystrophin gene. Importantly, DMD therapies assume that disease progression can be slowed by promoting the expression of truncated dystrophin comparable to what occurs in BMD patients. In this study, we explore similarities and differences in protein trajectories over time between BMD and DMD serum, and explore proteins related to motor function performance. Methods Serum samples collected from 34 BMD patients, in a prospective longitudinal 3-year study, and 19 DMD patients, were analyzed by using Data Independent Acquisition Tandem Mass Spectrometry (DIA-MS). Subsequent normalization, linear mixed effects model was employed to identify proteins associated with physical tests and dystrophin expression in skeletal muscle. Analysis was also performed to explore the discrepancy between DMD and BMD biomarker abundance trajectories over time. Results Linear mixed effects models identified 20 proteins with altered longitudinal signatures between DMD and BMD, including creatine kinase M-type (CKM) pyruvate kinase (PKM), fibrinogen gamma chain (FGG), lactate dehydrogenase B (LDHB) and alpha-2-macroglobulin (A2M). Furthermore, several proteins related to innate immune response were associated with motor function in BMD patients. In particular, A2M displayed an altered time-dependent decline in relation to dystrophin expression in the tibialis anterior muscle. Conclusions Our study revealed differences in the serum proteome between BMD and DMD, which comprises proteins involved in the immune response, extracellular matrix organization and hemostasis but not muscle leakage proteins significantly associated with disease progression in DMD. If further evaluated and validated, these biomarker candidates may offer means to monitor disease progression in BMD patients. A2M is of particular interest due to its association with dystrophin expression in BMD muscle and higher abundance in DMD patients in comparison to BMD. If validated, A2M could be used as a pharmacodynamic biomarker in therapeutic clinical trials aiming to restore dystrophin expression.
2024-05-01 | Enhancing Sarcolemmal Membrane Repair Using a Novel Protein Therapeutic Approach can Improve Membrane Integrity in Duchenne Muscular Dystrophy Cells and Mouse Models
Duchenne Muscular Dystrophy (DMD) is a fatal neuromuscular disease involving progressive cardiac and skeletal myocyte cell death and subsequent muscle degeneration. DMD and Becker muscular dystrophy (BMD) result from mutations in the dystrophin gene that compromise the structural integrity of the sarcolemma. While there has been important recent progress in the treatment of DMD, the currently available therapeutics have significant limitations. Thus, novel therapies that address the compromised sarcolemmal membrane integrity are an unmet medical need. Tripartite motif protein 72, or mitsugumin 53 (TRIM72/MG53), facilitates the sarcolemma repair response after disruption of the membrane. Loss of TRIM72/MG53 function in mice leads to a progressive myopathy. Exogenous delivery of recombinant human MG53 protein (rhMG53) can increase sarcolemmal membrane repair in many different cell types and ameliorate pathology in models of DMD and multiple limb girdle muscular dystrophies. Despite the promise of rhMG53 as a therapeutic invention the development of this protein to treat DMD has been complicated by findings showing that high levels of the protein correlate with metabolic dysfunction in animal models and some human patients. Deletion analysis of the major domains of the rhMG53 protein allowed us to design an improved version of rhMG53 called MyoTRIM. MyoTRIM contains amino acid replacements to eliminate metabolic effects and improve solubility while maintaining membrane repair effects. One set of modifications inactivate the E3 ligase activity of the protein, which revealed this function is dispensable for subcellular localization of the protein. TRIM72/MG53 is reported to mediate this effect by binding phosphatidylserine (PS) at membrane injury sites, so we demonstrate that MyoTRIM can bind PS-coated beads to illustrate that carboxy-terminal domains are required for effcient PS binding rather than the E3 ligase function. External application of MyoTRIM can increase membrane repair capacity in a variety of cell-based assays using DMD and BMD patient myoblasts and myotubes. We also establish that MyoTRIM can increase membrane repair and prevent eccentric contraction induced injury in a dystrophin deficient mouse model. Taken together, these results provide mechanistic insight into rhMG53 function and indicate that MyoTRIM can recapitulate the therapeutic effects on sarcolemmal membrane repair while eliminating E3 ligase activity and associated side effects. This work was supported by the Offce of the Assistant Secretary of Defense for Health Affairs through the Duchenne Muscular Dystrophy Research Program (DMDRP) under Translational Research Award HT9425-23-1-0940. The opinions, interpretations, conclusions, and recommendations are those of the author and are not necessarily endorsed by the Department of Defense. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
2019-08-06 | Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease
Abstract Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the transforming growth factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 – a locally acting, follistatin-based fusion protein – as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, activin A, activin B and growth differentiation factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness.
2015-05-05 | MicroRNAs modulated by local mIGF-1 expression in mdx dystrophic mice
Duchenne muscular dystrophy (DMD) is a X-linked genetic disease in which the absence of dystrophin leads to progressive lethal skeletal muscle degeneration. It has been demonstrated that among genes which are important for proper muscle development and function, micro-RNAs (miRNAs) play a crucial role. Moreover, altered levels of miRNAs were found in several muscular disorders, including DMD. A specific group of miRNAs, whose expression depends on dystrophin levels and whose deregulation explains several DMD pathogenetic traits, has been identified. Here, we addressed whether the anabolic activity of mIGF-1 on dystrophic muscle is associated with modulation of microRNAs expression. We demonstrated that some microRNAs are strictly linked to the dystrophin expression and are not modulated by mIGF-1 expression. In contrast, local expression of mIGF-1 promotes the modulation of other microRNAs, such as miR-206 and mir-24, along with the modulation of muscle specific genes, which are associated with maturation of regenerating fibers and with the stabilization of the differentiated muscle phenotype. These data suggest that mIGF-1, modifying the expression of some of the active players of muscle homeostasis, is able, even in absence of dystrophin expression, to activate circuitries that confer robustness to dystrophic muscle.
small molecules
2026-07-01 | Human Disposition, Metabolism, and Excretion of Sevasemten (EDG‐5506), a Selective Modulator of Fast Myosin in Healthy Volunteers
Abstract Sevasemten (EDG‐5506) is a novel, orally bioavailable, investigational small molecule designed to selectively modulate type II fast skeletal myosin with the goal of protecting dystrophic muscle from contraction‐induced injury. Sevasemten is in clinical development for the treatment of Becker and Duchenne muscular dystrophy. In the current Phase 1 study (NCT05730842), eight participants were dosed with a 20 mg single oral suspension dose of sevasemten containing approximately 500 µCi [ 14 C] sevasemten. Blood and urine samples were collected to evaluate the pharmacokinetics (PK), oral absorption, metabolism, and excretion (AME) of sevasemten and its metabolites. A second cohort of seven participants received a single 20 mg oral dose of sevasemten, followed 2 h later by a single dose of [ 14 C] sevasemten administered as a single intravenous (IV) bolus with approximately 1 µCi [ 14 C] sevasemten to determine absolute bioavailability. Sevasemten was excreted primarily in urine (52.1%) subsequent to CYP3A‐mediated metabolism, and 8.89% was eliminated in the feces, for a total of 61.0% recovered over 840 h post‐dose. Most of the recoverable radioactivity was excreted by 576 h (24 days). However, sevasemten total radioactivity in plasma and whole blood was characterized by a very slow elimination phase of 16.1–20.6 days; total recovery of radioactivity was not achieved. Sevasemten was well tolerated, with no serious adverse events or adverse events leading to study discontinuation. Sevasemten has favorable PK properties for once daily administration and continues to be investigated for the treatment of Becker and Duchenne muscular dystrophies.
2026-06-17 | Effects of sevasemten (EDG-5506) on safety, biomarkers, and functional measures in adults with Becker muscular dystrophy: results of a phase 1b, open-label study.
Sevasemten (EDG-5506) is an orally administered, investigational small molecule that selectively modulates fast muscle fibre contraction by inhibiting fast myosin ATPase. In animal models of Duchenne and Becker muscular dystrophy (DMD and BMD, respectively), sevasemten reduced the muscle contraction injury that leads to inflammation, fibrosis and muscle loss without affecting function. The aim of this study was to evaluate the long-term safety, tolerability, and pharmacokinetics (PK)/pharmacodynamics of sevasemten in adult participants with BMD who had already experienced a decline in function and would be anticipated to continue to decline based on natural history. This open-label, dose escalation, phase 1 b study (NCT05160415) was conducted at a single site and enrolled ambulatory adults with BMD aged 18-55 years; the study is completed. Eligible participants received 10 mg of sevasemten once daily (QD) for 8 weeks, followed by 15 mg QD for 4 months, 20 mg QD for 9 months, and 10 mg QD for 9 months. The primary objective was to assess the safety and tolerability of sevasemten in adults with BMD; endpoints included adverse events (AEs), PK, change from baseline in circulating biomarkers of muscle injury, as well as physical function measures. The study enrolled 12 adults with BMD. Sevasemten was well tolerated; all AEs were mild or moderate in severity and there were no serious AEs or AEs leading to discontinuation. Treatment with sevasemten was associated with reductions in circulating biomarkers of muscle injury that were evident within 4 weeks and sustained for up to 24 months. Physical function, as assessed by North Star Ambulatory Assessment (NSAA), was stable over 24 months. Sevasemten treatment for up to 24 months in adults with BMD was well tolerated and associated with durable reductions in muscle injury biomarkers, consistent with preclinical studies and near maximal with the 10 mg dose, as well as functional stabilisation. Further clinical development is ongoing. Edgewise Therapeutics, Inc.
2026-05-20 | Heart failure guideline-directed medical therapy in young adults with dystrophin-related cardiomyopathy: the HOPE-MD registry
BACKGROUND: Duchenne (DMD) and Becker (BMD) muscular dystrophies often progress to dilated cardiomyopathy and heart failure with reduced ejection fraction (HFrEF), a major cause of death in affected patients. Although guideline-directed medical therapy (GDMT) improves HFrEF outcomes, its real-world use in dystrophinopathies is poorly defined. We assessed GDMT utilization and optimization in the study population. METHODS: HOPE-MD is a European, multicentre, retrospective registry including adults with genetically confirmed DMD or BMD and left ventricular ejection fraction (LVEF) ≤40%. GDMT was defined as concurrent use of a renin-angiotensin system inhibitor (RASi), beta-blocker, mineralocorticoid receptor antagonist (MRA), and sodium-glucose cotransporter-2 inhibitor (SGLT2i). Doses were categorized as target (≥100%), intermediate (50-99%), or low (<50%). RESULTS: Among 274 patients (age, 28 years; LVEF, 35%; DMD, 80%), 44 (16%) received GDMT at baseline, with only one quarter at ≥50% of the target dose. Underutilization was greatest for MRAs (n=140, 51%) and SGLT2i (n=60, 22%), whereas RASi (n=246, 90%) and beta-blockers (n=235, 86%) were frequently prescribed. After 24 months (n=141), 40% received GDMT, and 22% received ≥50% of the target dose, primarily through MRA and SGLT2i initiation/uptitration. Contraindications accounted for only a small proportion of undertreatment. At a median follow-up of 2.2 (1.7-2.6) years, optimized GDMT was not associated with a statistically significant difference in the rates of death or HF hospitalization compared with low-dose or no GDMT (adjusted HR 0.70, 95% CI 0.28-1.74). CONCLUSIONS: GDMT use and dose escalation were suboptimal in European patients with DMD/BMD and HFrEF.
2026-02-09 | (Z)-Endoxifen as a Modulator of Utrophin Pathways in Duchenne Muscular Dystrophy: A Mechanistic and Transcriptomic Perspective
Duchenne muscular dystrophy (DMD) is a fatal X-linked neuromuscular disorder caused by mutations in the dystrophin gene, leading to sarcolemmal instability, chronic calcium overload, mitochondrial dysfunction, inflammation, and fibrosis. These effects manifest clinically as muscle atrophy, loss of mobility, and respiratory and cardiac insufficiencies. Although gene-targeted approaches such as exon skipping and microdystrophin delivery have advanced, their applicability is restricted by genotype and adverse effects. Thus, reasonably safe, effective therapies remain a critical unmet need. (Z)‑endoxifen, the (Z)-isomer of endoxifen, is the principal active metabolite of tamoxifen, exhibiting higher potency in protein kinase C (PKC) inhibition than tamoxifen and regulating various protein activities differently than tamoxifen. This pharmacologic profile positions endoxifen to address multiple DMD pathomechanisms simultaneously. Recent literature supports the prior hypothesis that endoxifen exerts pleiotropic benefits in DMD. Transcriptomic and preclinical evidence shows that endoxifen may have superior effects to tamoxifen in reversing DMD signatures given available dosing regimens. Additionally, pathway level insights support endoxifen activation of myogenesis, oxidative phosphorylation, estrogen receptor beta (ERβ) activation, and inhibition of pro-inflammatory and epithelial-to-mesenchymal transition (EMT) pathways in DMD. These findings suggest (Z)‑endoxifen acts on utrophin-linked regulatory axes potentially contributing to functional compensation for dystrophin deficiency, providing justification for its development as a mutation-agnostic DMD therapeutic approach. Keywords: gene expression regulation, selective estrogen receptor modulators, skeletal muscle regeneration, pharmacologic action mechanism, Becker muscular dystrophy
2026-01-01 | Response to the Letter Regarding "If Becker Muscular Dystrophy Initially Manifests with Heart Disease and Rhabdomyolysis, Neurological Work-up is Imperative"
We thank Dr. Finsterer for his interest in our case report (1) and for responding to the questions and comments.The patient presented with only mildly elevated creatine kinase (CPK) levels, and both his leg press strength and hand grip strength were within the normal limits, although patients with Becker muscular dystrophy (BMD) typically exhibit skeletal muscle symptoms preceding myocardial dysfunction.Although the patient did not undergo a neurological examination at the time of rhabdomyolysis onset, mild skeletal muscle symptoms, such as mild muscle atrophy or diminished tendon reflexes, might have been detected, as Dr. Finsterer suggested.Dilated cardiomyopathy and left ventricular noncompaction (LVNC) have both been reported in patients with Duchenne muscular dystrophy and BMD (2, 3).In our case, the echocardiographic findings did not meet the criteria for LVNC and the explanted heart showed no prominent trabeculation or intertrabecular thrombus formation.The development of rhabdomyolysis remains necessary even after transplantation.Rhabdomyolysis has been reported to occur with immunosuppressive agents in patients who have undergone organ or bone marrow transplantation (4-7).Our patient received standard tacrolimus-based triple immunosuppression ( tacrolimus, mycophenolate mofetil, and prednisolone), and mycophenolate mofetil was switched to everolimus at 8 months post-transplant due to a cytomegalovirus infection and neutropenia.Currently, the CPK levels fluctuate between approximately 700 and 1,500 IU/L, and follow-up is being conducted with regular monitoring of the immunosuppressant blood concentrations to prevent the development of rhabdomyolysis.Read-through therapy has been used in patients with dys-trophy and nonsense mutations, primarily in Europe.However, because it has not yet been approved in Japan, this therapy was not used in our patient.Finally, antibodies against dystrophin are formed in the transplanted hearts of these patients (8).Although we did not measure the antibodies in this case, no recurrent rejection episodes or graft loss were observed.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
7 orphan drug designations for Duchenne and Becker muscular dystrophy.
7 orphan drug designations for Duchenne and Becker muscular dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
type II fast skeletal myosin inhibitor | small molecules | FDA | Edgewise Therapeutics | |
Trodusquemine HCl | small molecules | FDA | — | Revidia Therapeutics. Inc. |
(+)-Epicatechin | small molecules | FDA | Epirium Bio Inc. | |
nandrolone | small molecules | FDA | — | Sarcomed AB |
L-aminocarnityl-succinyl-leucyl-argininal-diethylacetal | peptides | FDA | — | CepTor Corporation |
Recombinant human anti-GDF-8 (growth and differentiation factor-8) antibody | antibodies | FDA | Wyeth Pharmaceuticals, Inc. | |
Oxandrolone | small molecules | FDA | — | Savient Pharmaceuticals, Inc. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.