RARE DISEASE
Limb-girdle muscular dystrophy
Limb-girdle muscular dystrophy
Limb-girdle muscular dystrophy
Synonyms: LGMD
Synonyms: LGMD
Synonyms: LGMD
Drug discovery
16
drugs
With orphan designations
Overview
Limb-girdle muscular dystrophy (LGMD) encompasses over 30 inherited neuromuscular disorders characterized by progressive proximal muscle weakness affecting hip and shoulder girdles. Caused by autosomal dominant or recessive mutations, it presents with variable onset (childhood to adulthood) and progression [1][7][16]. Cardiac/respiratory involvement occurs in specific subtypes, requiring multidisciplinary care [1][12]. No disease-modifying therapies exist, though emerging molecular treatments are under investigation [3][13][17].
Population
Affects both sexes equally, with combined prevalence estimates ranging from 1:14,500 to 1:123,000 [1][5][12]
LGMD2A (calpainopathy) accounts for 30% of cases, while sarcoglycanopathies and dysferlinopathies comprise 15-20% each [2][7]
Founder mutations increase subtype prevalence regionally (e.g., CAPN3 variants in Spain/Brazil, FKRP in Northern Europe) [2][5]
Therapies
Supportive care: Physical/occupational therapy, orthotics, and respiratory/cardiac monitoring [1][14][19]
Pharmacologic: Corticosteroids show limited efficacy in LGMD2C-F subtypes [1][17]
Experimental: Gene therapy (AAV-mediated hASM for LGMD2B), exon skipping, and CRISPR-Cas9 editing in preclinical stages [3][13][15]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
711 drug discovery papers about Limb-girdle muscular dystrophy, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
711 drug discovery papers about Limb-girdle muscular dystrophy, with 3 first-in-class and 6 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-30 | Safety, Tolerability, Pharmacokinetics, Food Effect of Ribitol, and Its Effect on QTcF in Healthy Adults: First-in-Human, Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Studies.
Limb-girdle muscle dystrophy Type R9 (LGMDR9), also known as LGMD Type 2I, is a rare genetic disease caused by partial loss of function of fukutin-related protein (FKRP) enzyme which glycosylates alpha-dystroglycan, thereby stabilizing myocytes during contraction. Hypoglycosylation leads to progressive muscle injury and impaired function including loss of ambulation. Ribitol is an endogenous pentose alcohol and precursor to CDP-ribitol, the substrate of FKRP. This first-in-human study demonstrated that ribitol was well tolerated when administered as single or multiple oral doses over 6 days to healthy adults. PK demonstrated dose-proportional increases in exposure from 0.5 to 15 g (therapeutic dose 9 and 12 g BID for patients weighing >30 to ≤50 kg and >50 kg, respectively); t½ was 9-13 h. A high-fat meal did not affect overall oral bioavailability; indicating ribitol may be taken without regard to food intake. A dedicated QT study using ribitol 21 g revealed no concentration-dependent QTcF prolongation and clinically significant QTcF prolongation was excluded over the entire range of exposures in the study, up to 351.9 µg/mL. Assay sensitivity was demonstrated with the expected effect of moxifloxacin. These results support further development of ribitol for the treatment of LGMDR9.
2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle
Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.
2026-05-19 | The flavanol (-)-epicatechin induced different histological features and myogenic protein levels in triceps, gastrocnemius and plantaris of δ-sarcoglycan-deficient mice.
Limb-girdle muscular dystrophies (LGMD) exhibit a wide range of disease severity, affecting various parts of the skeletal muscle to varying degrees. This may be associated with differences in the degeneration and regeneration processes in different muscles. We previously reported that muscles with different metabolic characteristics showed distinct levels of proteins involved in the muscle regeneration process in δ-sarcoglycan-deficient mice, a model for LGMDR6. These phenomena may be relevant to test potential therapeutic compounds in myopathies. In this study, we analyzed the effect of (-)-epicatechin (Epi), a flavanol enriched in cacao that has shown beneficial effects in skeletal muscle, in different muscles of the δ-sarcoglycan-deficient mice. Histochemical analysis showed that dystrophic triceps and gastrocnemius had a higher level of fibrosis than plantaris, and Epi reduced this. In addition, Epi increased the cross-sectional area of dystrophic triceps fibers, which was associated with a higher fusion index. In contrast, Epi reduced the index fusion in dystrophic plantaris. Western blot analysis demonstrates that Epi increases protein levels of Pax7, β-catenin, and myogenin in the dystrophic triceps and increases protein levels of β-catenin and myogenin in the gastrocnemius. In contrast, in the plantaris, none of the protein levels was modified. All these results suggest that muscles with different metabolic characteristics and physiological demands could respond differentially to pharmacological therapies in dystrophic muscles.
2026-05-06 | (-)-Epicatechin modulates skeletal muscle inflammatory response in a mouse model of Limb-Girdle Muscular Dystrophy 2F
Abstract Skeletal muscle possesses remarkable regenerative capacity. However, in limb-girdle muscular dystrophy-2F (LGMD2F), this capacity is compromised by persistent innate immune activation, whose transcriptional landscape remains unexplored. In parallel, (-)-Epicatechin has emerged as a promising compound with beneficial effects on muscle and notable anti-inflammatory properties. We therefore used (-)-Epicatechin treatment to test whether it can alleviate LGMD2F-associated transcriptional and immune dysregulation. Here we provide the first transcriptomic characterization of LGMD2F using the Sgcd ⁻/⁻ mouse model, along with the first RNA-sequencing-based evaluation of (-)-Epicatechin treatment. We profiled two functionally distinct muscles — the soleus and EDL — through bulk RNA-sequencing coupled with immune cell-deconvolution. Sgcd ⁻/⁻ muscles exhibited marked transcriptional dysregulation, more pronounced in the soleus and associated with enhanced innate immune signaling. (-)-Epicatechin induced a muscle- and genotype-dependent transcriptional response: in wild-type animals, the EDL displayed the highest number of differentially expressed transcripts, whereas in Sgcd ⁻/⁻ mice, the soleus showed the most prominent response. This shift was accompanied by downregulation of Toll-like receptor and RIG-I-like receptor pathways, along with suppression of NF-κB2 and interferon-stimulated genes. Together, these findings identify innate immune overactivation as a central feature of LGMD2F and reveal (-)-Epicatechin as a context-dependent modulator of muscle-specific transcriptional responses.
2026-04-27 | Heart Transplant in a Patient with Fukutin-Related-Protein Limb-Girdle-Muscular-Dystrophy and Severe Cardiomyopathy: A Case Study
Background/Purpose: Limb-Girdle-Muscular-Dystrophy R9 (LGMD R9) is caused by autosomal recessive mutations of the Fukutin-related protein (FKRP), leading to defective glycosylation of Alpha-dystroglycan. Patients with compound heterozygote mutations have a more severe course. Dilated cardiomyopathy (DCM) is frequent and can precede loss of ambulation by many years. Methods: A boy (10 years old) presented with difficulties in climbing stairs, fatigue, and limited walking distance. Serum-CK: 10.600 U/L. Genetic testing revealed compound heterozygote mutations in FKRP (c.947C>G and c.826C>A). Echocardiography showed DCM. Over 5 years. period muscle weakness progressed (6-minute walking test 200 m, North Star Ambulatory Assessment [NSAA]-score 20), increasing shortness of breath (SOB) on mild exercise (with normal pulmonary function tests and sleep studies), severe fatigue, and weight loss. This was accompanied by deterioration of his ejection fraction (LVEF) from 45 to 25% and progression of severe left ventricular dilatation from 45 to 69 mm despite maximal heart failure treatment (fourfold anticongestive medical treatment and regular Levosimendan infusions). Results: Decision for HTx was made following multidisciplinary and ethical discussion. The patient (15 years) underwent HTx with an uncomplicated course. Four months post-HTx, walking distance and motor activities improved (NSAA-Score +8). Cardiac function was normal. Six months after HTx, immunosuppressive therapy showed severe side effects (neutropenia, mucositis, weight loss) and motor function decline. Twelve months after HTx therapy with Vamorolon was started, followed by a reduction of CK level. Conclusion: HTx can be an option in patients with LGMD R9. SOB, loss of walking distance, and fatigue can be caused by heart failure due to DCM. In patients with mild neuromuscular involvement and end-stage DCM, long-term prognosis is closely linked to the possibility of a heart transplant. The long-term effect of corticosteroids on motor function needs to be further investigated in LGMD R9. Publication History Article published online: 27 April 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
cell therapies
2025-01-13 | Safety and Efficacy of Autologous Bone Marrow Derived Mononuclear Cell Transplant in the Management of Various Neurological Disorders.
Cerebral palsy (CP), traumatic spinal cord injury (SCI), and muscular dystrophy (MD), among the various other neurological disorders, are major global health problems because they are chronic disorders with no curative treatments at present. Current interventions aim to relieve symptoms alone and therefore emphasize the necessity for new approaches. This study aims to assess the safety and efficacy of autologous bone marrow-derived mononuclear cell (BM-MNC) therapy in patients with CP, traumatic SCI, and MD. Functional improvement and safety are the primary outcomes, while secondary outcomes include patient-reported improvement in quality of life. This was a single-arm, open-label prospective study conducted on 100 patients with CP, SCI, and MD at the GSVM Medical College, Kanpur, India. Bone marrow aspirates were processed via centrifugation, and autologous BM-MNCs were administered intrathecally or intramuscularly. Gross motor function classification system (GMFCS) for CP, the American spinal injury association (ASIA) motor score for SCI, and the north star assessment for limb girdle type dystrophies (NSAD) for MD were used for functional outcome assessment at baseline and at post-treatment cycles. Informed consent was obtained, and the study was approved by the ethics committee. Paired t-tests were used to analyze statistical significance (p<0.05). Functional improvements were significant with autologous BM-MNC therapy. Improved motor and cognitive function were shown in CP patients with reduced GMFCS scores (p<0.001). Upper and lower extremity ASIA motor scores improved markedly (p<0.001) in SCI patients. Stabilized muscle strength was seen in MD patients, with increased NSAD and activities of daily living (ADL) scores, suggesting slowing of the disease progression (p<0.019). Side effects were mild and transient. Autologous BM-MNC therapy appears to be a promising, minimally invasive option for patients with CP, SCI, and MD, which appears to markedly improve functional outcomes and quality of life and may therefore be relevant to clinical practice.
2023-08-11 | Modeling Sarcoglycanopathy in Danio rerio
Sarcoglycanopathies, also known as limb girdle muscular dystrophy 3-6, are rare muscular dystrophies characterized, although heterogeneous, by high disability, with patients often wheelchair-bound by late adolescence and frequently developing respiratory and cardiac problems. These diseases are currently incurable, emphasizing the importance of effective treatment strategies and the necessity of animal models for drug screening and therapeutic verification. Using the CRISPR/Cas9 genome editing technique, we generated and characterized δ-sarcoglycan and β-sarcoglycan knockout zebrafish lines, which presented a progressive disease phenotype that worsened from a mild larval stage to distinct myopathic features in adulthood. By subjecting the knockout larvae to a viscous swimming medium, we were able to anticipate disease onset. The δ-SG knockout line was further exploited to demonstrate that a δ-SG missense mutant is a substrate for endoplasmic reticulum-associated degradation (ERAD), indicating premature degradation due to protein folding defects. In conclusion, our study underscores the utility of zebrafish in modeling sarcoglycanopathies through either gene knockout or future knock-in techniques. These novel zebrafish lines will not only enhance our understanding of the disease's pathogenic mechanisms, but will also serve as powerful tools for phenotype-based drug screening, ultimately contributing to the development of a cure for sarcoglycanopathies.
2023-06-30 | The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
ABSTRACT Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphy’s Roth Large (MRL) strain has “super-healing” properties that reduce fibrosis. A comparative analysis of the Sgcg null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized “myoscaffolds”. Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from Sgcg −/− MRL and Sgcg −/− DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy. Brief Summary The extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy. Graphical Abstract
2022-07-08 | Generation of human myogenic progenitors from pluripotent stem cells for in vivo regeneration
Muscular dystrophy encompasses a large number of heterogeneous genetic disorders characterized by progressive and devastating muscle wasting. Cell-based replacement strategies aimed at promoting skeletal muscle regeneration represent a candidate therapeutic approach to treat muscular dystrophies. Due to the difficulties of obtaining large numbers of stem cells from a muscle biopsy as well as expanding these in vitro, pluripotent stem cells (PSCs) represent an attractive cell source for the generation of myogenic progenitors, given that PSCs can repeatedly produce large amounts of lineage-specific tissue, representing an unlimited source of cells for therapy. In this review, we focus on the progress to date on different methods for the generation of human PSC-derived myogenic progenitor cells, their regenerative capabilities upon transplantation, their potential for allogeneic and autologous transplantation, as well as the specific challenges to be considered for future therapeutic applications.
2022-05-23 | Generation of hiPSC-Derived Skeletal Muscle Cells: Exploiting the Potential of Skeletal Muscle-Derived hiPSCs
Cell therapies for muscle wasting disorders are on the verge of becoming a realistic clinical perspective. Muscle precursor cells derived from human induced pluripotent stem cells (hiPSCs) represent the key to unrestricted cell numbers indispensable for the treatment of generalized muscle wasting such as cachexia or intensive care unit (ICU)-acquired weakness. We asked how the cell of origin influences efficacy and molecular properties of hiPSC-derived muscle progenitor cells. We generated hiPSCs from primary muscle stem cells and from peripheral blood mononuclear cells (PBMCs) of the same donors (n = 4) and compared their molecular profiles, myogenic differentiation potential, and ability to generate new muscle fibers in vivo. We show that reprogramming into hiPSCs from primary muscle stem cells was faster and 35 times more efficient than from blood cells. Global transcriptome comparison revealed significant differences, but differentiation into induced myogenic cells using a directed transgene-free approach could be achieved with muscle- and PBMC-derived hiPSCs, and both cell types generated new muscle fibers in vivo. Differences in myogenic differentiation efficiency were identified with hiPSCs generated from individual donors. The generation of muscle-stem-cell-derived hiPSCs is a fast and economic method to obtain unrestricted cell numbers for cell-based therapies in muscle wasting disorders, and in this aspect are superior to blood-derived hiPSCs.
gene therapies
2026-07-16 | Limb-girdle Muscular Dystrophy Type 2I/R9: Future Gene Therapy Options of an Extremely Rare Fukutin Protein-related Dystroglycanopathy
Limb-girdle muscular dystrophy type 2I, now designated R9 (LGMD2I/R9), is an autosomal recessive dystroglycanopathy caused by biallelic pathogenic variants in the fukutin-related protein (FKRP) gene. Loss of FKRP glycosyltransferase activity disrupts the ribitol-phosphate-mediated glycosylation of alpha-dystroglycan, reducing matriglycan formation and weakening the link between the sarcolemma and the extracellular matrix. The resulting phenotype ranges from mild, adult-onset limb-girdle weakness to a severe congenital muscular dystrophy, and frequently includes dilated cardiomyopathy and restrictive respiratory failure. No disease-modifying treatment is currently licensed, and management remains supportive. Over the past decade, three broad experimental strategies have moved toward clinical evaluation: adeno-associated virus (AAV)-mediated gene replacement, small-molecule substrate supplementation with ribitol, and combinatorial approaches that pair gene replacement with muscle-anabolic transgenes such as follistatin. Registered early-phase AAV-FKRP programmes and the placebo-controlled FORTIFY trial of oral ribitol provide important translational context, but peer-reviewed clinical efficacy and long-term safety data remain limited; interim registry, conference and sponsor-reported findings should therefore be interpreted cautiously. This narrative review synthesises the molecular pathophysiology of FKRP-related dystroglycanopathy, appraises the natural history and outcome measures relevant to trial design, and critically evaluates the preclinical and early clinical evidence for gene-based and substrate-based therapies. It concludes with a discussion of unresolved translational barriers and a forward-looking assessment of the therapeutic pipeline for this ultra-rare neuromuscular disorder.
2026-06-18 | Clinical presentations and pathophysiological mechanisms of dystroglycanopathy: advancing therapeutic strategies.
Dystroglycanopathies are muscular dystrophies with varying clinical severities, ranging from congenital-onset to adult limb-girdle muscular dystrophy. Dystroglycanopathies are caused by a loss of function of the extracellular matrix receptor α-dystroglycan, a widely expressed cell-surface glycoprotein required for the formation and function of various muscle and non-muscle tissues. In severe clinical presentations, individuals with dystroglycanopathy experience, in addition to muscle weakness and cardiac involvement, structural ocular and CNS malformations, leading to intellectual disability and epilepsy. Currently, management is only symptomatic. Advances in the understanding of the pathophysiology and genetics have identified new therapeutic targets. Emerging therapeutic approaches, including adeno-associated virus gene therapy for limb-girdle muscular dystrophy associated with pathogenic variants in FKRP (the most common form of dystroglycanopathy) and ribitol-based therapies, are being evaluated in clinical trials and could expand treatment options.
2026-06-09 | Limb-girdle Muscular Dystrophies in a Single-center Adult Population: Clinical Spectrum and Genetic Findings (P8-9.006)
We describe clinical, genetic, and pathological features of a cohort of patients with LGMD followed at Montreal Neurological Institute-Hospital
2026-05-15 | Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
2026-05-04 | With Regard to the Expression Status of Sarcolemmal Aquaporin 4 in Human Muscular Dystrophies
ABSTRACT Human muscular dystrophies are inherited muscle‐wasting diseases caused by the various kinds of gene mutations. Among them, Duchenne muscular dystrophy (DMD) is a representative type. Before the discovery of the causative dystrophin gene of DMD, the fragile myofiber plasma membrane was thought to be the trigger of myofiber necrosis in DMD. Freeze‐fracture electron microscopy enabled us to observe the hydrophobic interior of the myofiber plasma membrane where the impressive structure called orthogonal array of particles (OAPs) was seen. Although the functional significance of this specific assembly was thought to be important, the precise function of this assembly was unknown at that time. After the OAPs function was found as a water channel aquaporin (AQP)4, the works about the sarcolemmal AQP4 expression were undertaken extensively. At the beginning of such works, altered sarcolemmal AQP4 expression was reported only in the dystrophinopathic muscles, and it was not described in other forms of human muscular dystrophies such as facioscapulohumeral and limb‐girdle muscular dystrophies in the early phase of research. However, the evidence which has been accumulated until now suggested that the reduced expression of sarcolemmal AQP4 was observed in a wide range of neuromuscular diseases such as dystrophinopathies, sarcoglycanopathies, dysferlinopathies, and even in neurogenic muscle atrophy.
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.
2025-11-16 | Mutations in Hsp40 co-chaperone change the canonical interdomain interactions stimulating LGMDD1 myopathy.
Limb-girdle muscular dystrophy D1 (LGMDD1) is a rare, dominantly inherited neuromuscular protein-misfolding chaperonopathy caused by mutations in the Hsp40 co-chaperone DNAJB6, primarily in the glycine-phenylalanine (GF) or J-domains. Currently, no treatments are available, and a challenge in understanding the disease is identifying a specific client protein for DNAJB6 in skeletal muscle. DNAJB6 has homology to the yeast DNAJ family member, Sis1. Our previous research indicated that LGMDD1 GF domain mutants in Sis1 exhibit substrate-specific effects, influenced by Hsp70 activity. Herein, we employed functional assays along with advanced molecular simulation studies to understand the regulatory interdomain interactions in disease-causing mutants of DNAJB6 that cause LGMDD1 myopathy. We found that disease-causing novel mutations in the J-domain mimic the chaperone's substrate-bound state, both directly by disrupting J-GF contacts and indirectly by destabilizing the J-CTD inhibitory linkage. Both routes converge on similar interdomain rearrangements, indicating a unified pathway, wherein this premature allosteric switch locks the chaperone in an inactive conformation, blocking productive interactions with substrates and Hsp70. These mechanistic insights enhance our understanding of LGMDD1 myopathy and facilitate the identification of potential treatment strategies for the future.
2025-07-14 | Mutations in Hsp40 co-chaperone change the unique canonical inter-domain interactions stimulating LGMDD1 myopathy.
Limb-girdle muscular dystrophy D1 (LGMDD1) is a rare, dominantly inherited neuromuscular disorder caused by mutations in the HSP40 co-chaperone DNAJB6, primarily in the GF or J-domains. Currently, no treatments are available, and a challenge in understanding the disease is identifying a specific client protein for DNAJB6 in skeletal muscle. Our previous research indicated that LGMDD1 GF domain mutants in Sis1 exhibit substrate-specific effects, influenced by HSP70 activity. Herein, we found that novel mutations in the J-domain similarly affected chaperone function. The J-domain mutants exhibited variable substrate processing, reduced binding affinity to client-substrate, and decreased stimulation of Ssa1 ATP hydrolysis, with these effects being substrate-conformer-specific. Our simulation studies noted differences in inter-domain interactions linked to the mutants, which influence the Hsp40-Hsp70 ATPase cycle. These mechanistic insights enhance our understanding of LGMDD1 myopathy and help to identify potential treatment strategies in the future. Recalibrating the inter-domain interface of the mutant protein could potentially serve as a key therapeutic strategy for LGMDD1 myopathy.
2025-06-24 | Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice.
The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25 kDa tetraspanin-like protein, anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, supporting the conclusions of biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in δ-sarcoglycanopathies, enabling substitution of δ-sarcoglycan by its homolog, ζ-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that ζ-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protects the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.
2025-05-01 | Sarcospan selectively interfaces with sarcoglycan subunits to stabilize the sarcolemma and prevent limb-girdle muscular dystrophy
Skeletal muscle possesses redundant molecular mechanisms that partially or fully compensate for loss of gene function and this information has been leveraged for development of novel therapies for the muscular dystrophies. Mutations in any one of the canonical sarcoglycan genes cause autosomal recessive Limb-girdle muscular dystrophies that are characterized by life-limiting skeletal muscle wasting and weakness. The objective of this study was to investigate the orthologous relationships within the sarcoglycan proteins and use these mechanisms to design new therapies for the Limb-girdle muscular dystrophies. The sarcoglycan complex canonically consists of alpha-, beta-, delta- and gamma-subunits. We show that sarcospan, a transmembrane scaffolding protein, mediates assembly of a compensatory complex in gamma-sarcoglycan deficient muscles, where gamma-sarcoglycan is replaced by zeta-sarcoglycan, a less abundant sarcoglycan. This alternative complex significantly improved skeletal muscle pathology in mouse models of Limb-girdle muscular dystrophy. Three-dimensional structural modeling of the compensatory sarcoglycan complex reveals that zeta-sarcoglycan maintains specific hydrophobic interactions with sarcospan and preserves overall quaternary arrangement. This compensatory complex protects the cell membrane from contraction-induced damage and all secondary consequences of disease. These findings demonstrate a novel mechanism stabilizing the complex by leveraging protein redundancy, with an important role for sarcospan in assembly and scaffolding of a compensatory complex in skeletal muscles. This work is supported by Sarepta Therapeutics This abstract was presented at the American Physiology Summit 2025 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.
other
2026-07-14 | PPMO therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.
The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF) gene. Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated limb-girdle muscular dystrophy type 2R or LGMDR2 (formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified in two independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that disrupt protein expression. In this study, we generated and characterized a novel mouse model for one of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaces the normal homologous mouse DNA. These mice exhibit aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this new model, we identified antisense oligonucleotides and then a PPMO that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle histology and function.
2026-06-15 | Correction of aberrant splicing caused by intronic CAPN3 pathogenic variants using RNA-targeted therapeutic strategies in limb-girdle muscular dystrophy type R1.
Pre-mRNA splicing is a highly precise process, and it is estimated that approximately 9%-11% of pathogenic variants in patients with rare genetic diseases are caused by non-coding variants that disrupt this mechanism. Developing targeted strategies to correct such splicing defects represents a promising therapeutic avenue. In this proof-of-concept study, we demonstrate the feasibility of rescuing distinct aberrant splicing patterns using tailored RNA-targeted approaches. We focused on two disease-causing intronic pathogenic variants in the CAPN3 gene (c.1193 + 30G > A and c.1354 + 5G > A), each leading to aberrant 5' splice site selection and premature termination codons. Using a faithful cellular minigene model, we designed and evaluated two variant-specific corrective strategies: a splice-switching oligonucleotide (SSO) to block a gained cryptic donor site (c.1193 + 30G > A), which restored canonical transcript levels to approximately 75% of wild-type; and an engineered U1 snRNA with compensatory base substitutions to restore a weakened canonical 5' splice site (c.1354 + 5G > A), which increased correct splicing from ~ 10% to nearly 60%. This work establishes a versatile therapeutic framework, providing compelling in vitro validation that precisely targeted RNA-based strategies can be successfully adapted to correct different types of splicing defects, offering a promising blueprint for the treatment of splicing-deficient genetic disorders.
2026-04-27 | Inflammation-Linked Muscle Atrophy in Limb Girdle Muscular Dystrophy R1 (LGMDR1): Insights into Disease Mechanisms.
Muscle atrophy is a major feature of Limb Girdle Muscular Dystrophy R1 (LGMDR1) patients, but its underlying molecular mechanisms have not been fully explored. While the ubiquitin-proteasome system (UPS) is known to be involved in muscle protein degradation, inflammation commonly observed in LGMDR1 patients may further activate the UPS. This study aimed to explore the role of inflammation in the muscle atrophy of LGMDR1 patients. Muscle biopsies from six confirmed LGMDR1 patients (with CAPN3 variants and reduced calpain-3 protein expression) were analyzed for atrophy-related markers, MuRF1 and Atrogin-1, using qRT-PCR and Western blotting. The expression of cytokines, TNF-α, IL-1β, and IL-6 was analyzed by qRT-PCR from muscle biopsies and by ELISA from serum samples. The NFκB, FOXO1, and FOXO3 gene expression was analyzed using qRT-PCR and Western blotting from muscle biopsies. Elevated TNF-α levels were associated with increased UPS activity, reflected by upregulated NFκB, FOXO1, MuRF1, and Atrogin-1 expression in LGMDR1. Our findings indicate that increased TNF-α expression is associated with muscle wasting in LGMDR1 patients by targeting UPS pathway mediators that activate ubiquitin ligases-MuRF1 and Atrogin-1. These findings suggest that targeting TNF-α signaling and its downstream factors may help develop therapeutic interventions to prevent muscle atrophy in LGMDR1 patients.
2025-11-03 | Abstract 4359395: Cardiac Function is Preserved in a Tissue-Engineered Model of LGMD2B
Background: Loss of dysferlin results in the rare, currently untreatable muscular dystrophy known as Limb Girdle Muscular Dystrophy 2B (LGMD2B). In LGMD2B mice, skeletal muscle undergoes progressive myopathy, whereas cardiac deficits only arise with advanced age, stress, or injury – suggesting the heart may harbor protective mechanisms that could guide future therapy developments. While dysferlin’s roles in membrane repair, Ca 2+ handling, and metabolism are well characterized in skeletal muscle, its function in the heart is poorly defined. We therefore engineered 3D LGMD2B cardiac and skeletal muscle tissues (“cardio- and myobundles”) to compare dysferlin’s differential roles in cardiac vs. skeletal muscle. Methods: Three healthy (HLT) and three LGMD2B human induced pluripotent stem cell (hiPSC) lines were differentiated into cardiomyocytes (hCMs) and muscle progenitor cells to generate cardio- and myobundles. After 2 weeks of culture, we performed isometric force tests, Ca 2+ transient imaging, and optical mapping of action potential propagation. To probe membrane repair capacity, osmotic shock injury (OSI) was induced with ~30 mOsm medium for 5 min followed by 15 min recovery, with contractile force recorded every minute. Tissues were also immunostained for sarcomere structure and dysferlin localization. Results: Both HLT and LGMD2B cardio- and myobundles exhibited aligned, cross-striated sarcomeric structure with dysferlin predominantly localized at the plasma membrane. Dysferlin-deficiency in myobundles resulted in a ~2-fold decrease in specific force generation and Ca 2+ transient amplitude. In contrast, loss of dysferlin did not affect cardiobundle specific force generation, Ca 2+ transient amplitude, conduction velocity, or action potential duration. Following OSI, cardiobundles lost >60 % of peak force independent of phenotype, while LGMD2B myobundles exhibited significantly greater force loss than HLT controls. Conclusions: We present the first in vitro tissue-engineered model of human LGMD2B cardiac muscle and show that, unlike engineered skeletal muscle and similar to in vivo findings, dysferlin deficiency does not compromise engineered cardiac tissue structure or function. Ongoing transcriptional analysis of HLT and LGMD2B cardiobundles vs. myobundles will probe putative cardioprotective pathways, with subsequent loss- and gain-of-function studies planned to validate novel therapeutic targets transferable to skeletal muscle.
2025-10-28 | Muscle transcriptomics of alpha-sarcoglycanopathy highlights inflammatory pathways driving disease.
Muscular dystrophies are a heterogeneous group of genetic disorders associated with an aberrant inflammatory response, that contributes to disease progression impairing regeneration and inducing fibrosis. Sarcoglycanopathies are recessively inherited limb-girdle muscular dystrophies (LGMDRs), in which the role of inflammation and its association with disease severity remains poorly understood, particularly in alpha-sarcoglycanopathy (LGMDR3). This study characterizes skeletal muscle and peripheral inflammatory signatures in 16 LGMDR3 patients and 8 unaffected individuals through bulk RNA sequencing with additional validation in Sgca-null mice. Patients were classified into mild and severe groups based on alpha sarcoglycan (SGCA) expression in muscle biopsy. Peripheral immunophenotype was assessed via flow cytometry analysis of peripheral blood mononuclear cells (PBMC). Principal component analysis showed a clear separation of severe LGMDR3 from mild LGMDR3 and unaffected individuals, with the latter two groups overlapping. Unsupervised hierarchical clustering analysis of the most variable genes identified distinct gene expression profiles between severe and mild LGMDR3 samples. Severe LGMD3 showed overexpression of innate immune system and T-cell activation pathways, with higher abundance of inflammatory infiltrate, mainly monocytes, cytotoxic T cells and dendritic cells. Notably, severe LGMDR3 were characterized by enrichment of M1-polarized macrophages and pro-inflammatory chemokines, whereas M2-polarized monocytes predominated in mild cases. Similar inflammatory profiles were observed in Sgca-null mice. PBMC analysis revealed significantly increased CD8+, TH1 CD4+ lymphocytes and activated monocytes in LGMDR3 patients compared with controls. Severe LGMDR3 patients additionally showed overexpression of genes governing fibrosis and muscle tissue regeneration and exhibited a clustering pattern similar to Duchenne muscular dystrophy patients. In conclusion, this study represents the first comprehensive characterization of LGMDR3 immunological profiles and demonstrated that inflammation plays a significant role in severe disease pathogenesis. The distinct immune signatures separating severe from mild cases provide a foundation for developing targeted anti-inflammatory therapies that may benefit severe LGMDR3 patients with severe phenotype.
small molecules
2026-07-30 | Safety, Tolerability, Pharmacokinetics, Food Effect of Ribitol, and Its Effect on QTcF in Healthy Adults: First-in-Human, Randomized, Double-Blind (Sponsor Unblinded), Placebo-Controlled Studies.
Limb-girdle muscle dystrophy Type R9 (LGMDR9), also known as LGMD Type 2I, is a rare genetic disease caused by partial loss of function of fukutin-related protein (FKRP) enzyme which glycosylates alpha-dystroglycan, thereby stabilizing myocytes during contraction. Hypoglycosylation leads to progressive muscle injury and impaired function including loss of ambulation. Ribitol is an endogenous pentose alcohol and precursor to CDP-ribitol, the substrate of FKRP. This first-in-human study demonstrated that ribitol was well tolerated when administered as single or multiple oral doses over 6 days to healthy adults. PK demonstrated dose-proportional increases in exposure from 0.5 to 15 g (therapeutic dose 9 and 12 g BID for patients weighing >30 to ≤50 kg and >50 kg, respectively); t½ was 9-13 h. A high-fat meal did not affect overall oral bioavailability; indicating ribitol may be taken without regard to food intake. A dedicated QT study using ribitol 21 g revealed no concentration-dependent QTcF prolongation and clinically significant QTcF prolongation was excluded over the entire range of exposures in the study, up to 351.9 µg/mL. Assay sensitivity was demonstrated with the expected effect of moxifloxacin. These results support further development of ribitol for the treatment of LGMDR9.
2026-06-21 | Consistent MYORG and STRADB Downregulation in DMD and LGMD: Rationale for Deoxygalactonojirimycin Repurposing in Dystrophic and Aging Muscle
Abstract Background MYORG (myogenesis-regulating glycosidase) and STRADB (STE20-related kinase adapter protein beta) were previously identified as activity-mediated skeletal muscle genes with potential roles in frailty and sarcopenia. We hypothesized that, if these genes are sustained by neuromuscular contractile activity, their expression should be consistently downregulated in muscular dystrophies, conditions defined by progressive muscle degeneration and secondary functional disuse. Methods We performed a systematic cross-dataset transcriptomic analysis of five publicly available GEO microarray datasets of human skeletal muscle. Discovery analysis was conducted in GSE3307 (Affymetrix HG-U133A/B; samples spanning DMD, LGMD2A/B/I, BMD, FSHD, JDM, ALS, AQM versus healthy controls). Independent external validation was performed in GSE38417 (HG-U133 Plus 2.0, DMD; n=16/6), GSE11681 (HG-U133A/B, LGMD2A; n=8-10/9-10), GSE465 (HG-U95Av2/B/C, multi-disease), and GSE1007 (HG-U95B/C/E, DMD; n=10-11/11). Raw CEL files underwent array-level quality assessment using NUSE and RLE diagnostics prior to normalization. Seven poor-quality arrays were excluded (none from Control, DMD, or LGMD groups). Remaining arrays were processed by robust multi-array average (RMA) normalization, and differential expression was assessed by limma with Benjamini-Hochberg FDR correction. Results MYORG was significantly downregulated in DMD (log2 fold-change [logFC] = -0.93, adj.P<0.001), LGMD2A (logFC = -0.82, adj.P<0.01), LGMD2B (logFC = -1.01, adj.P<0.01), and LGMD2I (logFC = -1.03, adj.P<0.01) in GSE3307. STRADB was significantly reduced in DMD (logFC = -0.33, adj.P<0.05) and showed a near-significant trend in LGMD2I (logFC = - 0.42, adj.P = 0.061). MYORG downregulation in DMD was independently replicated in GSE38417 (logFC = -1.40, adj.P<0.001) and GSE1007 (logFC = -0.80, adj.P<0.001). STRADB was also significantly downregulated in GSE38417 DMD (logFC = -0.45, adj.P<0.001). Deoxygalactonojirimycin, an iminosugar and an FDA/EMA-approved pharmacological chaperone (migalastat/Galafold) for Fabry disease, has been reported to be a specific molecular interactor that stabilizes MYORG protein in skeletal muscle. Conclusions This multi-dataset study further supports the role of MYORG and STRADB as activity-sensitive muscle genes that are robustly downregulated in DMD and LGMD. The pharmacological interaction between migalastat and MYORG provides a mechanistically grounded rationale for investigating this approved agent as an adjunct therapy in muscular dystrophies, in combination with the existing standard of care. This also supports active investigation of iminosugar analogs to target MYORG as potential therapeutics for improving skeletal muscle function in dystrophies, frailty, and sarcopenia.
2026-05-19 | The flavanol (-)-epicatechin induced different histological features and myogenic protein levels in triceps, gastrocnemius and plantaris of δ-sarcoglycan-deficient mice.
Limb-girdle muscular dystrophies (LGMD) exhibit a wide range of disease severity, affecting various parts of the skeletal muscle to varying degrees. This may be associated with differences in the degeneration and regeneration processes in different muscles. We previously reported that muscles with different metabolic characteristics showed distinct levels of proteins involved in the muscle regeneration process in δ-sarcoglycan-deficient mice, a model for LGMDR6. These phenomena may be relevant to test potential therapeutic compounds in myopathies. In this study, we analyzed the effect of (-)-epicatechin (Epi), a flavanol enriched in cacao that has shown beneficial effects in skeletal muscle, in different muscles of the δ-sarcoglycan-deficient mice. Histochemical analysis showed that dystrophic triceps and gastrocnemius had a higher level of fibrosis than plantaris, and Epi reduced this. In addition, Epi increased the cross-sectional area of dystrophic triceps fibers, which was associated with a higher fusion index. In contrast, Epi reduced the index fusion in dystrophic plantaris. Western blot analysis demonstrates that Epi increases protein levels of Pax7, β-catenin, and myogenin in the dystrophic triceps and increases protein levels of β-catenin and myogenin in the gastrocnemius. In contrast, in the plantaris, none of the protein levels was modified. All these results suggest that muscles with different metabolic characteristics and physiological demands could respond differentially to pharmacological therapies in dystrophic muscles.
2026-05-06 | (-)-Epicatechin modulates skeletal muscle inflammatory response in a mouse model of Limb-Girdle Muscular Dystrophy 2F
Abstract Skeletal muscle possesses remarkable regenerative capacity. However, in limb-girdle muscular dystrophy-2F (LGMD2F), this capacity is compromised by persistent innate immune activation, whose transcriptional landscape remains unexplored. In parallel, (-)-Epicatechin has emerged as a promising compound with beneficial effects on muscle and notable anti-inflammatory properties. We therefore used (-)-Epicatechin treatment to test whether it can alleviate LGMD2F-associated transcriptional and immune dysregulation. Here we provide the first transcriptomic characterization of LGMD2F using the Sgcd ⁻/⁻ mouse model, along with the first RNA-sequencing-based evaluation of (-)-Epicatechin treatment. We profiled two functionally distinct muscles — the soleus and EDL — through bulk RNA-sequencing coupled with immune cell-deconvolution. Sgcd ⁻/⁻ muscles exhibited marked transcriptional dysregulation, more pronounced in the soleus and associated with enhanced innate immune signaling. (-)-Epicatechin induced a muscle- and genotype-dependent transcriptional response: in wild-type animals, the EDL displayed the highest number of differentially expressed transcripts, whereas in Sgcd ⁻/⁻ mice, the soleus showed the most prominent response. This shift was accompanied by downregulation of Toll-like receptor and RIG-I-like receptor pathways, along with suppression of NF-κB2 and interferon-stimulated genes. Together, these findings identify innate immune overactivation as a central feature of LGMD2F and reveal (-)-Epicatechin as a context-dependent modulator of muscle-specific transcriptional responses.
2026-04-27 | Heart Transplant in a Patient with Fukutin-Related-Protein Limb-Girdle-Muscular-Dystrophy and Severe Cardiomyopathy: A Case Study
Background/Purpose: Limb-Girdle-Muscular-Dystrophy R9 (LGMD R9) is caused by autosomal recessive mutations of the Fukutin-related protein (FKRP), leading to defective glycosylation of Alpha-dystroglycan. Patients with compound heterozygote mutations have a more severe course. Dilated cardiomyopathy (DCM) is frequent and can precede loss of ambulation by many years. Methods: A boy (10 years old) presented with difficulties in climbing stairs, fatigue, and limited walking distance. Serum-CK: 10.600 U/L. Genetic testing revealed compound heterozygote mutations in FKRP (c.947C>G and c.826C>A). Echocardiography showed DCM. Over 5 years. period muscle weakness progressed (6-minute walking test 200 m, North Star Ambulatory Assessment [NSAA]-score 20), increasing shortness of breath (SOB) on mild exercise (with normal pulmonary function tests and sleep studies), severe fatigue, and weight loss. This was accompanied by deterioration of his ejection fraction (LVEF) from 45 to 25% and progression of severe left ventricular dilatation from 45 to 69 mm despite maximal heart failure treatment (fourfold anticongestive medical treatment and regular Levosimendan infusions). Results: Decision for HTx was made following multidisciplinary and ethical discussion. The patient (15 years) underwent HTx with an uncomplicated course. Four months post-HTx, walking distance and motor activities improved (NSAA-Score +8). Cardiac function was normal. Six months after HTx, immunosuppressive therapy showed severe side effects (neutropenia, mucositis, weight loss) and motor function decline. Twelve months after HTx therapy with Vamorolon was started, followed by a reduction of CK level. Conclusion: HTx can be an option in patients with LGMD R9. SOB, loss of walking distance, and fatigue can be caused by heart failure due to DCM. In patients with mild neuromuscular involvement and end-stage DCM, long-term prognosis is closely linked to the possibility of a heart transplant. The long-term effect of corticosteroids on motor function needs to be further investigated in LGMD R9. Publication History Article published online: 27 April 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
cell therapies
2025-01-13 | Safety and Efficacy of Autologous Bone Marrow Derived Mononuclear Cell Transplant in the Management of Various Neurological Disorders.
Cerebral palsy (CP), traumatic spinal cord injury (SCI), and muscular dystrophy (MD), among the various other neurological disorders, are major global health problems because they are chronic disorders with no curative treatments at present. Current interventions aim to relieve symptoms alone and therefore emphasize the necessity for new approaches. This study aims to assess the safety and efficacy of autologous bone marrow-derived mononuclear cell (BM-MNC) therapy in patients with CP, traumatic SCI, and MD. Functional improvement and safety are the primary outcomes, while secondary outcomes include patient-reported improvement in quality of life. This was a single-arm, open-label prospective study conducted on 100 patients with CP, SCI, and MD at the GSVM Medical College, Kanpur, India. Bone marrow aspirates were processed via centrifugation, and autologous BM-MNCs were administered intrathecally or intramuscularly. Gross motor function classification system (GMFCS) for CP, the American spinal injury association (ASIA) motor score for SCI, and the north star assessment for limb girdle type dystrophies (NSAD) for MD were used for functional outcome assessment at baseline and at post-treatment cycles. Informed consent was obtained, and the study was approved by the ethics committee. Paired t-tests were used to analyze statistical significance (p<0.05). Functional improvements were significant with autologous BM-MNC therapy. Improved motor and cognitive function were shown in CP patients with reduced GMFCS scores (p<0.001). Upper and lower extremity ASIA motor scores improved markedly (p<0.001) in SCI patients. Stabilized muscle strength was seen in MD patients, with increased NSAD and activities of daily living (ADL) scores, suggesting slowing of the disease progression (p<0.019). Side effects were mild and transient. Autologous BM-MNC therapy appears to be a promising, minimally invasive option for patients with CP, SCI, and MD, which appears to markedly improve functional outcomes and quality of life and may therefore be relevant to clinical practice.
2023-08-11 | Modeling Sarcoglycanopathy in Danio rerio
Sarcoglycanopathies, also known as limb girdle muscular dystrophy 3-6, are rare muscular dystrophies characterized, although heterogeneous, by high disability, with patients often wheelchair-bound by late adolescence and frequently developing respiratory and cardiac problems. These diseases are currently incurable, emphasizing the importance of effective treatment strategies and the necessity of animal models for drug screening and therapeutic verification. Using the CRISPR/Cas9 genome editing technique, we generated and characterized δ-sarcoglycan and β-sarcoglycan knockout zebrafish lines, which presented a progressive disease phenotype that worsened from a mild larval stage to distinct myopathic features in adulthood. By subjecting the knockout larvae to a viscous swimming medium, we were able to anticipate disease onset. The δ-SG knockout line was further exploited to demonstrate that a δ-SG missense mutant is a substrate for endoplasmic reticulum-associated degradation (ERAD), indicating premature degradation due to protein folding defects. In conclusion, our study underscores the utility of zebrafish in modeling sarcoglycanopathies through either gene knockout or future knock-in techniques. These novel zebrafish lines will not only enhance our understanding of the disease's pathogenic mechanisms, but will also serve as powerful tools for phenotype-based drug screening, ultimately contributing to the development of a cure for sarcoglycanopathies.
2023-06-30 | The super-healing MRL strain promotes muscle growth in muscular dystrophy through a regenerative extracellular matrix
ABSTRACT Genetic background shifts the severity of muscular dystrophy. In mice, the DBA/2J strain confers a more severe muscular dystrophy phenotype, whereas the Murphy’s Roth Large (MRL) strain has “super-healing” properties that reduce fibrosis. A comparative analysis of the Sgcg null model of Limb Girdle Muscular Dystrophy in the DBA/2J versus MRL strain showed the MRL background was associated with greater myofiber regeneration and reduced structural degradation of muscle. Transcriptomic profiling of dystrophic muscle in the DBA/2J and MRL strains indicated strain-dependent expression of the extracellular matrix (ECM) and TGF-β signaling genes. To investigate the MRL ECM, cellular components were removed from dystrophic muscle sections to generate decellularized “myoscaffolds”. Decellularized myoscaffolds from dystrophic mice in the protective MRL strain had significantly less deposition of collagen and matrix-bound TGF-β1 and TGF-β3 throughout the matrix, and dystrophic myoscaffolds from the MRL background were enriched in myokines. C2C12 myoblasts were seeded onto decellularized matrices from Sgcg −/− MRL and Sgcg −/− DBA/2J matrices. Acellular myoscaffolds from the dystrophic MRL background induced myoblast differentiation and growth compared to dystrophic myoscaffolds from the DBA/2J matrices. These studies establish that the MRL background also generates its effect through a highly regenerative ECM, which is active even in muscular dystrophy. Brief Summary The extracellular matrix of the super-healing MRL mouse strain harbors regenerative myokines that improve skeletal muscle growth and function in muscular dystrophy. Graphical Abstract
2022-07-08 | Generation of human myogenic progenitors from pluripotent stem cells for in vivo regeneration
Muscular dystrophy encompasses a large number of heterogeneous genetic disorders characterized by progressive and devastating muscle wasting. Cell-based replacement strategies aimed at promoting skeletal muscle regeneration represent a candidate therapeutic approach to treat muscular dystrophies. Due to the difficulties of obtaining large numbers of stem cells from a muscle biopsy as well as expanding these in vitro, pluripotent stem cells (PSCs) represent an attractive cell source for the generation of myogenic progenitors, given that PSCs can repeatedly produce large amounts of lineage-specific tissue, representing an unlimited source of cells for therapy. In this review, we focus on the progress to date on different methods for the generation of human PSC-derived myogenic progenitor cells, their regenerative capabilities upon transplantation, their potential for allogeneic and autologous transplantation, as well as the specific challenges to be considered for future therapeutic applications.
2022-05-23 | Generation of hiPSC-Derived Skeletal Muscle Cells: Exploiting the Potential of Skeletal Muscle-Derived hiPSCs
Cell therapies for muscle wasting disorders are on the verge of becoming a realistic clinical perspective. Muscle precursor cells derived from human induced pluripotent stem cells (hiPSCs) represent the key to unrestricted cell numbers indispensable for the treatment of generalized muscle wasting such as cachexia or intensive care unit (ICU)-acquired weakness. We asked how the cell of origin influences efficacy and molecular properties of hiPSC-derived muscle progenitor cells. We generated hiPSCs from primary muscle stem cells and from peripheral blood mononuclear cells (PBMCs) of the same donors (n = 4) and compared their molecular profiles, myogenic differentiation potential, and ability to generate new muscle fibers in vivo. We show that reprogramming into hiPSCs from primary muscle stem cells was faster and 35 times more efficient than from blood cells. Global transcriptome comparison revealed significant differences, but differentiation into induced myogenic cells using a directed transgene-free approach could be achieved with muscle- and PBMC-derived hiPSCs, and both cell types generated new muscle fibers in vivo. Differences in myogenic differentiation efficiency were identified with hiPSCs generated from individual donors. The generation of muscle-stem-cell-derived hiPSCs is a fast and economic method to obtain unrestricted cell numbers for cell-based therapies in muscle wasting disorders, and in this aspect are superior to blood-derived hiPSCs.
gene therapies
2026-07-16 | Limb-girdle Muscular Dystrophy Type 2I/R9: Future Gene Therapy Options of an Extremely Rare Fukutin Protein-related Dystroglycanopathy
Limb-girdle muscular dystrophy type 2I, now designated R9 (LGMD2I/R9), is an autosomal recessive dystroglycanopathy caused by biallelic pathogenic variants in the fukutin-related protein (FKRP) gene. Loss of FKRP glycosyltransferase activity disrupts the ribitol-phosphate-mediated glycosylation of alpha-dystroglycan, reducing matriglycan formation and weakening the link between the sarcolemma and the extracellular matrix. The resulting phenotype ranges from mild, adult-onset limb-girdle weakness to a severe congenital muscular dystrophy, and frequently includes dilated cardiomyopathy and restrictive respiratory failure. No disease-modifying treatment is currently licensed, and management remains supportive. Over the past decade, three broad experimental strategies have moved toward clinical evaluation: adeno-associated virus (AAV)-mediated gene replacement, small-molecule substrate supplementation with ribitol, and combinatorial approaches that pair gene replacement with muscle-anabolic transgenes such as follistatin. Registered early-phase AAV-FKRP programmes and the placebo-controlled FORTIFY trial of oral ribitol provide important translational context, but peer-reviewed clinical efficacy and long-term safety data remain limited; interim registry, conference and sponsor-reported findings should therefore be interpreted cautiously. This narrative review synthesises the molecular pathophysiology of FKRP-related dystroglycanopathy, appraises the natural history and outcome measures relevant to trial design, and critically evaluates the preclinical and early clinical evidence for gene-based and substrate-based therapies. It concludes with a discussion of unresolved translational barriers and a forward-looking assessment of the therapeutic pipeline for this ultra-rare neuromuscular disorder.
2026-06-18 | Clinical presentations and pathophysiological mechanisms of dystroglycanopathy: advancing therapeutic strategies.
Dystroglycanopathies are muscular dystrophies with varying clinical severities, ranging from congenital-onset to adult limb-girdle muscular dystrophy. Dystroglycanopathies are caused by a loss of function of the extracellular matrix receptor α-dystroglycan, a widely expressed cell-surface glycoprotein required for the formation and function of various muscle and non-muscle tissues. In severe clinical presentations, individuals with dystroglycanopathy experience, in addition to muscle weakness and cardiac involvement, structural ocular and CNS malformations, leading to intellectual disability and epilepsy. Currently, management is only symptomatic. Advances in the understanding of the pathophysiology and genetics have identified new therapeutic targets. Emerging therapeutic approaches, including adeno-associated virus gene therapy for limb-girdle muscular dystrophy associated with pathogenic variants in FKRP (the most common form of dystroglycanopathy) and ribitol-based therapies, are being evaluated in clinical trials and could expand treatment options.
2026-06-09 | Limb-girdle Muscular Dystrophies in a Single-center Adult Population: Clinical Spectrum and Genetic Findings (P8-9.006)
We describe clinical, genetic, and pathological features of a cohort of patients with LGMD followed at Montreal Neurological Institute-Hospital
2026-05-15 | Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
2026-05-04 | With Regard to the Expression Status of Sarcolemmal Aquaporin 4 in Human Muscular Dystrophies
ABSTRACT Human muscular dystrophies are inherited muscle‐wasting diseases caused by the various kinds of gene mutations. Among them, Duchenne muscular dystrophy (DMD) is a representative type. Before the discovery of the causative dystrophin gene of DMD, the fragile myofiber plasma membrane was thought to be the trigger of myofiber necrosis in DMD. Freeze‐fracture electron microscopy enabled us to observe the hydrophobic interior of the myofiber plasma membrane where the impressive structure called orthogonal array of particles (OAPs) was seen. Although the functional significance of this specific assembly was thought to be important, the precise function of this assembly was unknown at that time. After the OAPs function was found as a water channel aquaporin (AQP)4, the works about the sarcolemmal AQP4 expression were undertaken extensively. At the beginning of such works, altered sarcolemmal AQP4 expression was reported only in the dystrophinopathic muscles, and it was not described in other forms of human muscular dystrophies such as facioscapulohumeral and limb‐girdle muscular dystrophies in the early phase of research. However, the evidence which has been accumulated until now suggested that the reduced expression of sarcolemmal AQP4 was observed in a wide range of neuromuscular diseases such as dystrophinopathies, sarcoglycanopathies, dysferlinopathies, and even in neurogenic muscle atrophy.
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.
2025-11-16 | Mutations in Hsp40 co-chaperone change the canonical interdomain interactions stimulating LGMDD1 myopathy.
Limb-girdle muscular dystrophy D1 (LGMDD1) is a rare, dominantly inherited neuromuscular protein-misfolding chaperonopathy caused by mutations in the Hsp40 co-chaperone DNAJB6, primarily in the glycine-phenylalanine (GF) or J-domains. Currently, no treatments are available, and a challenge in understanding the disease is identifying a specific client protein for DNAJB6 in skeletal muscle. DNAJB6 has homology to the yeast DNAJ family member, Sis1. Our previous research indicated that LGMDD1 GF domain mutants in Sis1 exhibit substrate-specific effects, influenced by Hsp70 activity. Herein, we employed functional assays along with advanced molecular simulation studies to understand the regulatory interdomain interactions in disease-causing mutants of DNAJB6 that cause LGMDD1 myopathy. We found that disease-causing novel mutations in the J-domain mimic the chaperone's substrate-bound state, both directly by disrupting J-GF contacts and indirectly by destabilizing the J-CTD inhibitory linkage. Both routes converge on similar interdomain rearrangements, indicating a unified pathway, wherein this premature allosteric switch locks the chaperone in an inactive conformation, blocking productive interactions with substrates and Hsp70. These mechanistic insights enhance our understanding of LGMDD1 myopathy and facilitate the identification of potential treatment strategies for the future.
2025-07-14 | Mutations in Hsp40 co-chaperone change the unique canonical inter-domain interactions stimulating LGMDD1 myopathy.
Limb-girdle muscular dystrophy D1 (LGMDD1) is a rare, dominantly inherited neuromuscular disorder caused by mutations in the HSP40 co-chaperone DNAJB6, primarily in the GF or J-domains. Currently, no treatments are available, and a challenge in understanding the disease is identifying a specific client protein for DNAJB6 in skeletal muscle. Our previous research indicated that LGMDD1 GF domain mutants in Sis1 exhibit substrate-specific effects, influenced by HSP70 activity. Herein, we found that novel mutations in the J-domain similarly affected chaperone function. The J-domain mutants exhibited variable substrate processing, reduced binding affinity to client-substrate, and decreased stimulation of Ssa1 ATP hydrolysis, with these effects being substrate-conformer-specific. Our simulation studies noted differences in inter-domain interactions linked to the mutants, which influence the Hsp40-Hsp70 ATPase cycle. These mechanistic insights enhance our understanding of LGMDD1 myopathy and help to identify potential treatment strategies in the future. Recalibrating the inter-domain interface of the mutant protein could potentially serve as a key therapeutic strategy for LGMDD1 myopathy.
2025-06-24 | Sarcospan protects against LGMD R5 via remodeling of the sarcoglycan complex composition in dystrophic mice.
The dystrophin-glycoprotein complex (DGC) is composed of peripheral and integral membrane proteins at the muscle cell membrane that link the extracellular matrix with the intracellular cytoskeleton. While it is well established that genetic mutations that disrupt the structural integrity of the DGC result in numerous muscular dystrophies, the 3D structure of the complex has remained elusive. Two recent elegant cryoEM structures of the DGC illuminate its molecular architecture and reveal the unique structural placement of sarcospan (SSPN) within the complex. SSPN, a 25 kDa tetraspanin-like protein, anchors β-dystroglycan to the β-, γ- and δ-sarcoglycan trimer, supporting the conclusions of biochemical studies that SSPN is a core element for DGC assembly and stabilization. Here, we advance these studies by revealing that SSPN provides scaffolding in δ-sarcoglycanopathies, enabling substitution of δ-sarcoglycan by its homolog, ζ-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that ζ-sarcoglycan preserves protein-protein interactions with the sarcospan, sarcoglycans, dystroglycan, and dystrophin. The structural integrity of the complex maintains myofiber attachment to the extracellular matrix and protects the cell membrane from contraction-induced damage. These findings demonstrate that sarcospan prevents limb-girdle muscular dystrophy R5 by remodeling of the sarcoglycan complex composition.
2025-05-01 | Sarcospan selectively interfaces with sarcoglycan subunits to stabilize the sarcolemma and prevent limb-girdle muscular dystrophy
Skeletal muscle possesses redundant molecular mechanisms that partially or fully compensate for loss of gene function and this information has been leveraged for development of novel therapies for the muscular dystrophies. Mutations in any one of the canonical sarcoglycan genes cause autosomal recessive Limb-girdle muscular dystrophies that are characterized by life-limiting skeletal muscle wasting and weakness. The objective of this study was to investigate the orthologous relationships within the sarcoglycan proteins and use these mechanisms to design new therapies for the Limb-girdle muscular dystrophies. The sarcoglycan complex canonically consists of alpha-, beta-, delta- and gamma-subunits. We show that sarcospan, a transmembrane scaffolding protein, mediates assembly of a compensatory complex in gamma-sarcoglycan deficient muscles, where gamma-sarcoglycan is replaced by zeta-sarcoglycan, a less abundant sarcoglycan. This alternative complex significantly improved skeletal muscle pathology in mouse models of Limb-girdle muscular dystrophy. Three-dimensional structural modeling of the compensatory sarcoglycan complex reveals that zeta-sarcoglycan maintains specific hydrophobic interactions with sarcospan and preserves overall quaternary arrangement. This compensatory complex protects the cell membrane from contraction-induced damage and all secondary consequences of disease. These findings demonstrate a novel mechanism stabilizing the complex by leveraging protein redundancy, with an important role for sarcospan in assembly and scaffolding of a compensatory complex in skeletal muscles. This work is supported by Sarepta Therapeutics This abstract was presented at the American Physiology Summit 2025 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.
other
2026-07-14 | PPMO therapy for dysferlinopathy induces pseudoexon skipping and restoration of functional protein.
The dysferlinopathies are a spectrum of autosomal recessive muscle diseases caused by mutations in the dysferlin gene (DYSF) gene. Clinical manifestations vary from asymptomatic hyperCKemia to severe muscle pathology and loss of muscle function. These are designated limb-girdle muscular dystrophy type 2R or LGMDR2 (formerly LGMD2B or Miyoshi myopathy). Among other functions, dysferlin is crucial for plasma membrane repair and maintenance of intracellular calcium homeostasis. In previous studies, we identified in two independent point mutations deep within introns that cause aberrant DYSF mRNA splicing and the inclusion of pseudoexons within transcripts that disrupt protein expression. In this study, we generated and characterized a novel mouse model for one of these mutations (within DYSF intron 44). In these mice, a segment of human DYSF DNA containing the mutant intronic sequence flanked by surrounding human exon sequences replaces the normal homologous mouse DNA. These mice exhibit aberrant Dysf pre-mRNA splicing, pseudoexon inclusion, loss of DYSF protein expression, and muscle pathology similar to that observed in patients. Using this new model, we identified antisense oligonucleotides and then a PPMO that blocks the mouse Dysf pre-mRNA splicing complexes from binding the mutant pre-mRNA, thereby restoring nearly normal muscle histology and function.
2026-06-15 | Correction of aberrant splicing caused by intronic CAPN3 pathogenic variants using RNA-targeted therapeutic strategies in limb-girdle muscular dystrophy type R1.
Pre-mRNA splicing is a highly precise process, and it is estimated that approximately 9%-11% of pathogenic variants in patients with rare genetic diseases are caused by non-coding variants that disrupt this mechanism. Developing targeted strategies to correct such splicing defects represents a promising therapeutic avenue. In this proof-of-concept study, we demonstrate the feasibility of rescuing distinct aberrant splicing patterns using tailored RNA-targeted approaches. We focused on two disease-causing intronic pathogenic variants in the CAPN3 gene (c.1193 + 30G > A and c.1354 + 5G > A), each leading to aberrant 5' splice site selection and premature termination codons. Using a faithful cellular minigene model, we designed and evaluated two variant-specific corrective strategies: a splice-switching oligonucleotide (SSO) to block a gained cryptic donor site (c.1193 + 30G > A), which restored canonical transcript levels to approximately 75% of wild-type; and an engineered U1 snRNA with compensatory base substitutions to restore a weakened canonical 5' splice site (c.1354 + 5G > A), which increased correct splicing from ~ 10% to nearly 60%. This work establishes a versatile therapeutic framework, providing compelling in vitro validation that precisely targeted RNA-based strategies can be successfully adapted to correct different types of splicing defects, offering a promising blueprint for the treatment of splicing-deficient genetic disorders.
2026-04-27 | Inflammation-Linked Muscle Atrophy in Limb Girdle Muscular Dystrophy R1 (LGMDR1): Insights into Disease Mechanisms.
Muscle atrophy is a major feature of Limb Girdle Muscular Dystrophy R1 (LGMDR1) patients, but its underlying molecular mechanisms have not been fully explored. While the ubiquitin-proteasome system (UPS) is known to be involved in muscle protein degradation, inflammation commonly observed in LGMDR1 patients may further activate the UPS. This study aimed to explore the role of inflammation in the muscle atrophy of LGMDR1 patients. Muscle biopsies from six confirmed LGMDR1 patients (with CAPN3 variants and reduced calpain-3 protein expression) were analyzed for atrophy-related markers, MuRF1 and Atrogin-1, using qRT-PCR and Western blotting. The expression of cytokines, TNF-α, IL-1β, and IL-6 was analyzed by qRT-PCR from muscle biopsies and by ELISA from serum samples. The NFκB, FOXO1, and FOXO3 gene expression was analyzed using qRT-PCR and Western blotting from muscle biopsies. Elevated TNF-α levels were associated with increased UPS activity, reflected by upregulated NFκB, FOXO1, MuRF1, and Atrogin-1 expression in LGMDR1. Our findings indicate that increased TNF-α expression is associated with muscle wasting in LGMDR1 patients by targeting UPS pathway mediators that activate ubiquitin ligases-MuRF1 and Atrogin-1. These findings suggest that targeting TNF-α signaling and its downstream factors may help develop therapeutic interventions to prevent muscle atrophy in LGMDR1 patients.
2025-11-03 | Abstract 4359395: Cardiac Function is Preserved in a Tissue-Engineered Model of LGMD2B
Background: Loss of dysferlin results in the rare, currently untreatable muscular dystrophy known as Limb Girdle Muscular Dystrophy 2B (LGMD2B). In LGMD2B mice, skeletal muscle undergoes progressive myopathy, whereas cardiac deficits only arise with advanced age, stress, or injury – suggesting the heart may harbor protective mechanisms that could guide future therapy developments. While dysferlin’s roles in membrane repair, Ca 2+ handling, and metabolism are well characterized in skeletal muscle, its function in the heart is poorly defined. We therefore engineered 3D LGMD2B cardiac and skeletal muscle tissues (“cardio- and myobundles”) to compare dysferlin’s differential roles in cardiac vs. skeletal muscle. Methods: Three healthy (HLT) and three LGMD2B human induced pluripotent stem cell (hiPSC) lines were differentiated into cardiomyocytes (hCMs) and muscle progenitor cells to generate cardio- and myobundles. After 2 weeks of culture, we performed isometric force tests, Ca 2+ transient imaging, and optical mapping of action potential propagation. To probe membrane repair capacity, osmotic shock injury (OSI) was induced with ~30 mOsm medium for 5 min followed by 15 min recovery, with contractile force recorded every minute. Tissues were also immunostained for sarcomere structure and dysferlin localization. Results: Both HLT and LGMD2B cardio- and myobundles exhibited aligned, cross-striated sarcomeric structure with dysferlin predominantly localized at the plasma membrane. Dysferlin-deficiency in myobundles resulted in a ~2-fold decrease in specific force generation and Ca 2+ transient amplitude. In contrast, loss of dysferlin did not affect cardiobundle specific force generation, Ca 2+ transient amplitude, conduction velocity, or action potential duration. Following OSI, cardiobundles lost >60 % of peak force independent of phenotype, while LGMD2B myobundles exhibited significantly greater force loss than HLT controls. Conclusions: We present the first in vitro tissue-engineered model of human LGMD2B cardiac muscle and show that, unlike engineered skeletal muscle and similar to in vivo findings, dysferlin deficiency does not compromise engineered cardiac tissue structure or function. Ongoing transcriptional analysis of HLT and LGMD2B cardiobundles vs. myobundles will probe putative cardioprotective pathways, with subsequent loss- and gain-of-function studies planned to validate novel therapeutic targets transferable to skeletal muscle.
2025-10-28 | Muscle transcriptomics of alpha-sarcoglycanopathy highlights inflammatory pathways driving disease.
Muscular dystrophies are a heterogeneous group of genetic disorders associated with an aberrant inflammatory response, that contributes to disease progression impairing regeneration and inducing fibrosis. Sarcoglycanopathies are recessively inherited limb-girdle muscular dystrophies (LGMDRs), in which the role of inflammation and its association with disease severity remains poorly understood, particularly in alpha-sarcoglycanopathy (LGMDR3). This study characterizes skeletal muscle and peripheral inflammatory signatures in 16 LGMDR3 patients and 8 unaffected individuals through bulk RNA sequencing with additional validation in Sgca-null mice. Patients were classified into mild and severe groups based on alpha sarcoglycan (SGCA) expression in muscle biopsy. Peripheral immunophenotype was assessed via flow cytometry analysis of peripheral blood mononuclear cells (PBMC). Principal component analysis showed a clear separation of severe LGMDR3 from mild LGMDR3 and unaffected individuals, with the latter two groups overlapping. Unsupervised hierarchical clustering analysis of the most variable genes identified distinct gene expression profiles between severe and mild LGMDR3 samples. Severe LGMD3 showed overexpression of innate immune system and T-cell activation pathways, with higher abundance of inflammatory infiltrate, mainly monocytes, cytotoxic T cells and dendritic cells. Notably, severe LGMDR3 were characterized by enrichment of M1-polarized macrophages and pro-inflammatory chemokines, whereas M2-polarized monocytes predominated in mild cases. Similar inflammatory profiles were observed in Sgca-null mice. PBMC analysis revealed significantly increased CD8+, TH1 CD4+ lymphocytes and activated monocytes in LGMDR3 patients compared with controls. Severe LGMDR3 patients additionally showed overexpression of genes governing fibrosis and muscle tissue regeneration and exhibited a clustering pattern similar to Duchenne muscular dystrophy patients. In conclusion, this study represents the first comprehensive characterization of LGMDR3 immunological profiles and demonstrated that inflammation plays a significant role in severe disease pathogenesis. The distinct immune signatures separating severe from mild cases provide a foundation for developing targeted anti-inflammatory therapies that may benefit severe LGMDR3 patients with severe phenotype.
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
16 orphan drug designations for Limb-girdle muscular dystrophy.
16 orphan drug designations for Limb-girdle muscular dystrophy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
primary human satellite cell-derived muscle stem cells derived from patients with genetic muscular dystrophy (CAPN3 c.550delA mutation) and engineered with CRISPR-Cas technology to express wild type CAPN3 protein | gene editing enzymes | FDA | 2025-11-06 | — | MyoPax GmbH |
Adeno-associated virus sector serotype rh74 containing the human SGCG gene | gene therapies | EMA | 2025-02-26 | — | Sarepta Therapeutics Ireland Limited |
Prednisone | small molecules | FDA | 2024-03-05 | — | Sarcomed AB |
Adeno-associated virus vector serotype 9/rh74 containing the human CAPN3 gene and a target sequence of cardiac-specific microRNA | gene therapies | EMA | 2023-10-13 | — | Atamyo Therapeutics |
Patidistrogene bexoparvovec | gene therapies | EMA | 2023-02-15 | — | Sarepta Therapeutics Ireland Limited |
Adeno-associated viral vector serotype 9 expressing fukutin-related protein | gene therapies | EMA | 2023-02-15 | — | AskBio France |
Adeno-associated virus serotype 8 expressing the human gamma-sarcoglycan gene | gene therapies | EMA | 2022-05-16 | — | Atamyo Therapeutics |
Adeno-associated virus serotype 9 expressing the human fukutin related protein and target sequence of the miR-208a | gene therapies | EMA | 2022-01-14 | — | Atamyo Therapeutics |
Adeno-associated virus serotype rh74 containing the human sarcoglycan beta gene | gene therapies | EMA | 2020-12-09 | — | Sarepta Therapeutics Ireland Limited |
Ribitol | small molecules | EMA | 2020-10-19 | — | Bridge Bio Europe B.V. |
nandrolone | small molecules | FDA | 2019-12-04 | — | Sarcomed AB |
ribitol | small molecules | FDA | 2019-01-16 | — | ML Bio Solutions, Inc. |
One, two, three, or four antisense oligonucleotides of Phosphorodiamidate morpholino oligomer combination that skips exons 4, 5, 6, and 7 of the gamma sarcoglycan (SGCG) gene | oligonucleotides | FDA | 2017-07-18 | — | Kurt+Peter Foundation |
Amino acids 2-506 of the wild-type human histidyl-tRNA synthetase [ATYR1940] | proteins | EMA | 2017-02-27 | — | Voisin Consulting Life Sciences |
Recombinant human histidyl-tRNA synthetase | proteins | FDA | 2017-02-23 | — | aTyr Pharma |
Angiotensin (1-7) | peptides | FDA | 2013-11-26 | — | Constant Therapeutics LLC |
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.