RARE DISEASE
Beta-sarcoglycan-related limb-girdle muscular dystrophy R4
Beta-sarcoglycan-related limb-girdle muscular dystrophy R4
Beta-sarcoglycan-related limb-girdle muscular dystrophy R4
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2E, Beta-sarcoglycan-related LGMD R4, Beta-sarcoglycanopathy, LGMD due to beta-sarcoglycan deficiency, LGMD type 2E, LGMD2E, Limb-girdle muscular dystrophy due to beta-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2E
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2E, Beta-sarcoglycan-related LGMD R4, Beta-sarcoglycanopathy, LGMD due to beta-sarcoglycan deficiency, LGMD type 2E, LGMD2E, Limb-girdle muscular dystrophy due to beta-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2E
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2E, Beta-sarcoglycan-related LGMD R4, Beta-sarcoglycanopathy, LGMD due to beta-sarcoglycan deficiency, LGMD type 2E, LGMD2E, Limb-girdle muscular dystrophy due to beta-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2E
Drug discovery
2
drugs
With orphan designations
Overview
Beta-sarcoglycan-related limb-girdle muscular dystrophy R4 (LGMD2E/R4) is an autosomal recessive neuromuscular disorder caused by mutations in the SGCB gene, leading to beta-sarcoglycan deficiency and destabilization of the dystrophin-glycoprotein complex. It presents in childhood/adolescence with progressive pelvic/shoulder girdle weakness, gait disturbances, and early loss of ambulation (typically by adolescence). Cardiomyopathy and respiratory insufficiency contribute to reduced life expectancy [2][12][19].
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
69 drug discovery papers about Beta-sarcoglycan-related limb-girdle muscular dystrophy R4, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
69 drug discovery papers about Beta-sarcoglycan-related limb-girdle muscular dystrophy R4, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
gene therapies
2025-12-25 | Transgene-induced cardiotoxicity in high-dose AAV gene transfer.
Gene delivery technologies based on adeno-associated virus (AAV) vectors have yielded promising results for the treatment of monogenic diseases. Preclinical studies and clinical trials have highlighted that infusing high AAV vector doses can induce cytotoxicity, resulting in the death of the patient in a few cases. In the wake of signs of cardiac symptoms in several human patients after gene transfer, we investigated the effects on the heart of systemic administration of high doses of AAV vectors expressing three different transgenes, corresponding to Duchenne muscular dystrophy, γ-sarcoglycanopathy, and fukutin-related protein deficiency. In all these cases, we observed the possibility of cardiotoxicity with high-dose injections that we related to transgene expression. Consequently, strategies reducing or preventing expression in the heart prevented the appearance of such cardiotoxicity and were also confirmed to be safe in non-human primates. Dissection of the mechanisms at stake revealed activation of stress cascades, leading to cardiomyocyte death due to protein overload or abnormal homeostasis of location or function of the specific protein. Our data highlighted a particular sensitivity of the heart to transgene expression, suggesting the importance of finely regulating the expression of transgenes in this vital organ in any gene therapy approach.
2025-12-20 | Additional Abstracts from the 2025 NMSG Meeting
Introduction: Limb-girdle muscular dystrophy 2E/R4 (LGMD2E/R4) is caused by pathogenetic variants in the beta-sarcoglycan (SGCB) gene leading to muscle loss.Bidridistrogene xeboparvovec, an adeno-associated virus vector that delivers the full-length SGCB transgene, has shown biologic efficacy and an acceptable safety profile.Objectives: To present VOYAGENE (SRP-9003-102; NCT05876780) 18-month data evaluating bidridistrogene xeboparvovec treatment in ambulatory and nonambulatory participants with LGMD2E/R4.Methods: Six participants (aged 17-29 years; 1 ambulatory and 5 nonambulatory; 2 females) received a single infusion of 7.41x10 13 vg/kg bidridistrogene xeboparvovec.Primary endpoints were treatment-emergent adverse events (TEAEs) and day 60 SGCB expression in muscle biopsy via immunofluorescence (IF) and Western blot (WB).Secondary endpoints were day 60 muscle vector genome copies, North Star Assessment for LGMD (NSAD), and Performance of Upper Limb (PUL) 2.0 scores by month 60.Other endpoints included changes in forced vital capacity (FVC), forced expiratory volume in one second (FEV 1 ), and creatine kinase (CK) levels through month 60.Results: No serious TEAEs, discontinuations, or deaths were noted.All participants had TEAEs; most were grade 1 (n=87/153) or 2 (n=63/153), with mostly mild/moderate treatment-related TEAEs (grade 1-2: 40/43; grade 3 [severe]: 3/43).At day 60, muscle biopsy showed increases in SGCB-positive fibers by IF and expression by WB; vector genome DNA was detected in myofibers in all participants.Over time NSAD, PUL 2.0, FVC, and FEV 1 remained stable and participants had reduced CK levels.Conclusions: These findings show partial restoration of SGCB expression after bidridistrogene xeboparvovec treatment in ambulatory and nonambulatory LGMD2E/R4 individuals.
2025-11-06 | Pharmacokinetic and Pharmacodynamic Evaluation of Bidridistrogene Xeboparvovec in an Aged Murine Model of Limb-Girdle Muscular Dystrophy Type 2E/R4.
Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is an ultra-rare autosomal recessive disorder caused by mutations in SGCB, the gene that encodes for β-sarcoglycan (SGCB), a component of the dystrophin-associated protein complex that stabilizes muscle fibers during contractions. Bidridistrogene xeboparvovec is an investigational adeno-associated virus-mediated gene transfer therapy designed to deliver a codon-optimized, full-length human SGCB and induce targeted expression of functional human SGCB protein. Interim safety and efficacy data from a clinical trial in patients with LGDM2E/R4 aged 4-15 years (NCT03652259) support further clinical development of bidridistrogene xeboparvovec. However, less is known about the effects of this agent in patients with more advanced LGMD2E/R4, who on average are older and heavier, which prompted their inclusion in studies VOYAGENE (NCT05876780, phase 1) and EMERGENE (NCT06246513, phase 3). In the preclinical study presented here, we delivered bidridistrogene xeboparvovec (0.185 × 1013 vg/kg, 0.37 × 1013 vg/kg, 0.74 × 1013 vg/kg, 1.85 × 1013 vg/kg, or 7.4 × 1013 vg/kg) to Sgcb-/- mice aged 27-42 weeks (n = 4 per dose) with age-matched saline-treated Sgcb-/- and C57BL/6J mice used as controls. Approximately 12 weeks after administration, we observed SGCB expression and found evidence of reduction in muscle fibrosis, reduction in muscle damage, and restoration of muscle force. Overall, a dose-dependent increase in vector exposure across tissue types was observed, with a nonlinear, exposure-dependent increase in both SGCB expression and functional improvement that reached saturation at 7.4 × 1013 vg/kg. Pharmacokinetic and pharmacodynamic analyses demonstrated a robust relationship between vector biodistribution, SGCB expression, and muscle force, further supporting clinical development of bidridistrogene xeboparvovec at the highest dose (7.4 × 1013 vg/kg), across a broad LGMD2E/R4 population and regardless of disease progression.
2025-05-13 | A prospective observational study assessing the functional disease progression of LGMDR4, betasarcoglycan-related limb girdle muscular dystrophy.
Limb-girdle muscular dystrophy (LGMD) R4, betasarcoglycanopathy, is a progressive muscle disease that frequently presents in childhood and results in loss of ambulation around 20 years of age. With interventional trials on the horizon it is essential to document functional disease progression using standardized performance outcome assessments (PerfO). We present a prospective longitudinal observational study of individuals recruited through both Nationwide Children's Hospital neuromuscular clinics and through outreach events held in an area with a high incidence of Founder variant (c.452C > G). PerfOs included the NorthStar Assessment for limb-girdle dystrophies (NSAD), Performance of Upper Limb (PUL), timed function tests, and spirometry, as appropriate. Forty-six individuals enrolled (aged 3-55 years) with 22 (55%) ambulant. Most PerfOs quantified change over time. We found heterogeneity of functional abilities at all ages. In our cohort, children's performance improved until around age 7, followed by a plateau until around 10-12 years. The ability to rise from the floor was the first milestone lost and was unable to be completed by anyone who took longer than 7.7 s on the 10-meter. Further, performance on select PerfOs were related to skills of functional independence, informing clinical care and data driven trial design. There is a great deal of functional heterogeneity. The selected PerfOs measured motor function and disease progression in individuals with LGMDR4, for the benefit of both data driven clinical management and clinical trial design.
2025-03-25 | Sarcoglycanopathies: From clinical diagnosis to new promising therapies
The sarcoglycanopathies are a severe form of limb girdle muscular dystrophy caused by mutations in the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD, leading to reduced or absent expression of the alpha-, beta-, gamma-, and delta-sarcoglycan proteins respectively. Most patients develop a severe disease starting in the first decade of life that progresses quickly and eventually leads to a loss of ambulation before the age of 20. However, there is a marked heterogeneity in the prognosis, and several patients develop a milder phenotype. The factors correlating with disease progression are not completely known, but recent data suggest that remaining protein expression can be a key factor. The diagnosis is confirmed by genetic studies, which are sometimes not confirmative in the case of identifying variants of unknown significance or just one variant. New tools to understand the potential pathogenesis of missense variants have been developed; these are helping in the diagnosis of these diseases. Additionally, recent data on muscle MRI have revealed a characteristic pattern of involvement that can also support the diagnosis of the disease. In recent years, data coming from international collaborative studies have allowed an understanding of disease progression; however, this is only through retrospective data. There are no prospective studies collecting longitudinal data on skeletal and respiratory muscle function or cardiac structure and function progression over time which is hampering the development of new drugs in the field. Clinical trials with gene therapy are underway or are being designed in some of the subtypes of sarcoglycanopathies to advance therapeutic management.
proteins
2024-09-09 | Sarcoglycans are Enriched at the Neuromuscular Junction in a Nerve-Dependent Manner
Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. These diseases are caused by mutations in genes coding for one of the four sarcoglycan transmembrane proteins, which form the sarcoglycan complex (SGC). Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that enrichment of sarcoglycans within the NMJ occurs only after innervation, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans' participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.
2022-11-01 | PGC-1α in the myofibers regulates the balance between myogenic and adipogenic progenitors affecting muscle regeneration
Skeletal muscle repair is accomplished by satellite cells (MuSCs) in cooperation with interstitial stromal cells (ISCs), but the relationship between the function of these cells and the metabolic state of myofibers remains unclear. This study reports an altered proportion of MuSCs and ISCs (including adipogenesis-regulatory cells; Aregs) induced by the transgenic overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the myofibers (MCK-PGC-1α mice). Although PGC-1α-driven increase of MuSCs does not accelerate muscle regeneration, myogenic progenitors isolated from MCK-PGC-1α mice and transplanted into intact and regenerating muscles are more prone to fuse with recipient myofibers than those derived from wild-type donors. Moreover, both young and aged MCK-PGC-1α animals exhibit reduced perilipin-positive areas when challenged with an adipogenic stimulus, demonstrating low propensity to accumulate adipocytes within the muscle. Overall, these results unveil that increased PGC-1α expression in the myofibers favors pro-myogenic and anti-adipogenic cell populations in the skeletal muscle.
2018-02-15 | The enzymatic processing of α-dystroglycan by MMP-2 is controlled by two anchoring sites distinct from the active site
Dystroglycan (DG) is a membrane receptor, belonging to the dystrophin-glycoprotein complex (DGC) and formed by two subunits, α-dystroglycan (α-DG) and β-dystroglycan (β -DG). The C-terminal domain of α-DG and the N-terminal extracellular domain of β -DG are connected, providing a link between the extracellular matrix and the cytosol. Under pathological conditions, such as cancer and muscular dystrophies, DG may be the target of metalloproteinases MMP-2 and MMP-9, contributing to disease progression. Previously, we reported that the C-terminal domain α-DG (483–628) domain is particularly susceptible to the catalytic activity of MMP-2; here we show that the α-DG 621–628 region is required to carry out its complete digestion, suggesting that this portion may represent a MMP-2 anchoring site. Following this observation, we synthesized an α-DG based-peptide, spanning the (613–651) C-terminal region. The analysis of the kinetic and thermodynamic parameters of the whole and the isolated catalytic domain of MMP-2 (cdMMP-2) has shown its inhibitory properties, indicating the presence of (at least) two binding sites for the peptide, both located within the catalytic domain, only one of the two being topologically distinct from the catalytic active groove. However, the different behavior between whole MMP-2 and cdMMP-2 envisages the occurrence of an additional binding site for the peptide on the hemopexin-like domain of MMP-2. Interestingly, mass spectrometry analysis has shown that α-DG (613–651) peptide is cleavable even though it is a very poor substrate of MMP-2, a feature that renders this molecule a promising template for developing a selective MMP-2 inhibitor.
2015-10-12 | Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping
Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional. We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.
2014-02-20 | Enhanced Ca2+ influx from STIM1–Orai1 induces muscle pathology in mouse models of muscular dystrophy
Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca2+ influx into myofibers leading to their death. Store-operated Ca2+ entry (SOCE) through sarcolemmal Ca2+ selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca2+ entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca2+ entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd−/−) mouse models of disease. Hence, Ca2+ influx across an unstable sarcolemma due to increased activity of a STIM1–Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
cell therapies
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
2019-05-09 | (Epi)genetic Modifications in Myogenic Stem Cells: From Novel Insights to Therapeutic Perspectives
The skeletal muscle is considered to be an ideal target for stem cell therapy as it has an inherent regenerative capacity. Upon injury, the satellite cells, muscle stem cells that reside under the basal lamina of the myofibres, start to differentiate in order to reconstitute the myofibres while maintaining the initial stem cell pool. In recent years, it has become more and more evident that epigenetic mechanisms such as histon modifications, DNA methylations and microRNA modulations play a pivatol role in this differentiation process. By understanding the mechanisms behind myogenesis, researchers are able to use this knowledge to enhance the differentiation and engraftment potential of different muscle stem cells. Besides manipulation on an epigenetic level, recent advances in the field of genome-engineering allow site-specific modifications in the genome of these stem cells. Combining epigenetic control of the stem cell fate with the ability to site-specifically correct mutations or add genes for further cell control, can increase the use of stem cells as treatment of muscular dystrophies drastically. In this review, we will discuss the advances that have been made in genome-engineering and the epigenetic regulation of muscle stem cells and how this knowledge can help to get stem cell therapy to its full potential.
2017-07-27 | Human dental pulp pluripotent-like stem cells promote wound healing and muscle regeneration
Dental pulp represents an easily accessible autologous source of adult stem cells. A subset of these cells, named dental pulp pluripotent-like stem cells (DPPSC), shows high plasticity and can undergo multiple population doublings, making DPPSC an appealing tool for tissue repair or maintenance.DPPSC were harvested from the dental pulp of third molars extracted from young patients. Growth factors released by DPPSC were analysed using antibody arrays. Cells were cultured in specific differentiation media and their endothelial, smooth and skeletal muscle differentiation potential was evaluated. The therapeutic potential of DPPSC was tested in a wound healing mouse model and in two genetic mouse models of muscular dystrophy (Scid/mdx and Sgcb-null Rag2-null γc-null).DPPSC secreted several growth factors involved in angiogenesis and extracellular matrix deposition and improved vascularisation in all three murine models. Moreover, DPPSC stimulated re-epithelialisation and ameliorated collagen deposition and organisation in healing wounds. In dystrophic mice, DPPSC engrafted in the skeletal muscle of both dystrophic murine models and showed integration in muscular fibres and vessels. In addition, DPPSC treatment resulted in reduced fibrosis and collagen content, larger cross-sectional area of type II fast-glycolytic fibres and infiltration of higher numbers of proangiogenic CD206+ macrophages.Overall, DPPSC represent a potential source of stem cells to enhance the wound healing process and slow down dystrophic muscle degeneration.
2015-03-09 | PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence
Abstract Mesoangioblasts are vessel-associated progenitor cells that show therapeutic promise for the treatment of muscular dystrophy. Mesoangioblasts have the ability to undergo skeletal muscle differentiation and cross the blood vessel wall regardless of the developmental stage at which they are isolated. Here we show that PW1/Peg3 is expressed at high levels in mesoangioblasts obtained from mouse, dog and human tissues and its level of expression correlates with their myogenic competence. Silencing PW1/Peg3 markedly inhibits myogenic potential of mesoangioblasts in vitro through MyoD degradation. Moreover, lack of PW1/Peg3 abrogates mesoangioblast ability to cross the vessel wall and to engraft into damaged myofibres through the modulation of the junctional adhesion molecule-A. We conclude that PW1/Peg3 function is essential for conferring proper mesoangioblast competence and that the determination of PW1/Peg3 levels in human mesoangioblasts may serve as a biomarker to identify the best donor populations for therapeutic application in muscular dystrophies.
2013-12-01 | A Special Population of Regulatory T Cells Potentiates Muscle Repair
Long recognized to be potent suppressors of immune responses, Foxp3+CD4+ regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
small molecules
2025-01-08 | Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy-Assessment of Patient's Primary Myotubes.
Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is a rare disease that currently has no cure. It is caused by defects in the SGCB gene, mainly missense mutations, which cause the impairment of the sarcoglycan complex, membrane fragility, and progressive muscle degeneration. Here, we studied the fate of some β-sarcoglycan (β-SG) missense mutants, confirming that, like α-SG missense mutants, they are targeted for degradation through the ubiquitin-proteasome system. These data, collected using HEK-293 cells expressing either the I119F- or Y184C mutants of β-SG, were subsequently confirmed in primary myotubes derived from an LGMD2E/R4 patient carrying a homozygous I92T mutation. The knowledge that β-SG with an amino acid substitution shares a pathway of degradation with α-SG mutants, allowed us to explore the pharmacological approach successfully tested in LGMD2D/R3. Several CFTR correctors, particularly corrector C17, preserved β-SG mutants from degradation and promoted localization at the sarcolemma of the entire SG complex. The presence of the complex, despite containing a mutated subunit, improved sarcolemma integrity, as evidenced by the reduced creatine kinase release from myotubes under hypoosmotic stress. These results suggest that β-SG missense mutants undergo proteasomal degradation as α-SG mutants, and that CFTR correctors, particularly C17, may be used as a potential therapeutic option for recovering and stabilizing the SG complex in patients with sarcoglycanopathies.
2023-01-16 | Targeting ryanodine receptors to treat human diseases
This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger in all living organisms. From C. elegans to mammals, Ca2+ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca2+ overload can result in loss of function and death. Intracellular Ca2+ release channels evolved to safely provide large, rapid Ca2+ signals without exposure to toxic extracellular Ca2+. RyRs are intracellular Ca2+ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR-mediated intracellular Ca2+ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer's disease, posttraumatic stress disorder, and Huntington's disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.
2020-03-06 | Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery
Sarcoglycanopathies are rare limb girdle muscular dystrophies, still incurable, even though symptomatic treatments may slow down the disease progression. Most of the disease-causing defects are missense mutations leading to a folding defective protein, promptly removed by the cell's quality control, even if possibly functional. Recently, we repurposed small molecules screened for cystic fibrosis as potential therapeutics in sarcoglycanopathy. Indeed, cystic fibrosis transmembrane regulator (CFTR) correctors successfully recovered the defective sarcoglycan-complex in vitro. Our aim was to test the combined administration of some CFTR correctors with C17, the most effective on sarcoglycans identified so far, and evaluate the stability of the rescued sarcoglycan-complex. We treated differentiated myogenic cells from both sarcoglycanopathy and healthy donors, evaluating the global rescue and the sarcolemma localization of the mutated protein, by biotinylation assays and western blot analyses. We observed the additive/synergistic action of some compounds, gathering the first ideas on possible mechanism/s of action. Our data also suggest that a defective α-sarcoglycan is competent for assembly into the complex that, if helped in cell traffic, can successfully reach the sarcolemma. In conclusion, our results strengthen the idea that CFTR correctors, acting probably as proteostasis modulators, have the potential to progress as therapeutics for sarcoglycanopathies caused by missense mutations.
2018-02-08 | Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model
// Yuko Iwata 1 , Yoshimi Katayama 2, 5 , Yasushi Okuno 3 and Shigeo Wakabayashi 4, 6 1 Departments of Molecular Physiology and Clinical Research, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan 2 Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Higashimatsuyama, Saitama, Japan 3 Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4 Departments of Molecular Physiology and Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan 5 Present affiliation: Biological Research Laboratories, Nissan Chemical Industries, Ltd, Shiraoka, Saitama, Japan 6 Present affiliation: Department of Pharmocology, Osaka Medical Collage, Takatsuki, Osaka, Japan Correspondence to: Yuko Iwata, email: yukoiwat@ncvc.go.jp Keywords: cardiomyopathy; muscular dystrophy; Ca2+ influx; Ca2+-permeable channel; therapy; Gerotarget Received: January 26, 2018 Accepted: February 01, 2018 Epub: February 08, 2018 Published: March 06, 2018 ABSTRACT Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca 2+ -entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca 2+ entry through both mouse and human TRPV2, with IC 50 of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca 2+ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy.
2013-03-19 | Leaky ryanodine receptors in β-sarcoglycan deficient mice: a potential common defect in muscular dystrophy.
Disruption of the sarcolemma-associated dystrophin-glycoprotein complex underlies multiple forms of muscular dystrophy, including Duchenne muscular dystrophy and sarcoglycanopathies. A hallmark of these disorders is muscle weakness. In a murine model of Duchenne muscular dystrophy, mdx mice, cysteine-nitrosylation of the calcium release channel/ryanodine receptor type 1 (RyR1) on the skeletal muscle sarcoplasmic reticulum causes depletion of the stabilizing subunit calstabin1 (FKBP12) from the RyR1 macromolecular complex. This results in a sarcoplasmic reticular calcium leak via defective RyR1 channels. This pathological intracellular calcium leak contributes to reduced calcium release and decreased muscle force production. It is unknown whether RyR1 dysfunction occurs also in other muscular dystrophies. To test this we used a murine model of Limb-Girdle muscular dystrophy, deficient in β-sarcoglycan (Sgcb-/-). Skeletal muscle RyR1 from Sgcb-/- deficient mice were oxidized, nitrosylated, and depleted of the stabilizing subunit calstabin1, which was associated with increased open probability of the RyR1 channels. Sgcb-/- deficient mice exhibited decreased muscle specific force and calcium transients, and displayed reduced exercise capacity. Treating Sgcb-/- mice with the RyR stabilizing compound S107 improved muscle specific force, calcium transients, and exercise capacity. We have previously reported similar findings in mdx mice, a murine model of Duchenne muscular dystrophy. Our data suggest that leaky RyR1 channels may underlie multiple forms of muscular dystrophy linked to mutations in genes encoding components of the dystrophin-glycoprotein complex. A common underlying abnormality in calcium handling indicates that pharmacological targeting of dysfunctional RyR1 could be a novel therapeutic approach to improve muscle function in Limb-Girdle and Duchenne muscular dystrophies.
other
2023-01-27 | Activated Oncostatin M signaling drives cancer-associated skeletal muscle wasting
Summary Progressive weakness and muscle loss are associated with multiple chronic conditions including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy, however, available anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1 . OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.
2022-08-29 | Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene
Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.
2008-03-11 | A phase I/IItrial of MYO‐029 in adult subjects with muscular dystrophy
Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy).This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential dose-escalation cohorts, each receiving MYO-029 or placebo (Cohort 1 at 1 mg/kg; Cohort 2 at 3 mg/kg; Cohort 3 at 10 mg/kg; Cohort 4 at 30 mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO-029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject-reported outcomes, magnetic resonance imaging studies, dual-energy radiographic absorptiometry studies, and muscle biopsy.MYO-029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30 mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO-029 was supported by a trend in a limited number of subjects toward increased muscle size using dual-energy radiographic absorptiometry and muscle histology.This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered.
2006-07-05 | Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy.
Myostatin (MSTN) is a muscle-specific secreted peptide that functions to limit muscle growth through an autocrine regulatory feedback loop. Loss of MSTN activity in cattle, mice, and humans leads to a profound phenotype of muscle overgrowth, associated with more and larger fibers and enhanced regenerative capacity. Deletion of MSTN in the mdx mouse model of Duchenne muscular dystrophy enhances muscle mass and reduces disease severity. In contrast, loss of MSTN activity in the dyW/dyW mouse model of laminin-deficient congenital muscular dystrophy, a much more severe and lethal disease model, does not improve all aspects of muscle pathology. Here we examined disease severity associated with myostatin (mstn-/-) deletion in mice nullizygous for delta-sarcoglycan (scgd-/-), a model of limb-girdle muscular dystrophy. Early loss of MSTN activity achieved either by monoclonal antibody administration or by gene deletion each improved muscle mass, regeneration, and reduced fibrosis in scgd-/- mice. However, antibody-mediated inhibition of MSTN in late-stage dystrophic scgd-/- mice did not improve disease. These findings suggest that MSTN inhibition may benefit muscular dystrophy when instituted early or if disease is relatively mild but that MSTN inhibition in severely affected or late-stage disease may be ineffective.
gene therapies
2025-12-25 | Transgene-induced cardiotoxicity in high-dose AAV gene transfer.
Gene delivery technologies based on adeno-associated virus (AAV) vectors have yielded promising results for the treatment of monogenic diseases. Preclinical studies and clinical trials have highlighted that infusing high AAV vector doses can induce cytotoxicity, resulting in the death of the patient in a few cases. In the wake of signs of cardiac symptoms in several human patients after gene transfer, we investigated the effects on the heart of systemic administration of high doses of AAV vectors expressing three different transgenes, corresponding to Duchenne muscular dystrophy, γ-sarcoglycanopathy, and fukutin-related protein deficiency. In all these cases, we observed the possibility of cardiotoxicity with high-dose injections that we related to transgene expression. Consequently, strategies reducing or preventing expression in the heart prevented the appearance of such cardiotoxicity and were also confirmed to be safe in non-human primates. Dissection of the mechanisms at stake revealed activation of stress cascades, leading to cardiomyocyte death due to protein overload or abnormal homeostasis of location or function of the specific protein. Our data highlighted a particular sensitivity of the heart to transgene expression, suggesting the importance of finely regulating the expression of transgenes in this vital organ in any gene therapy approach.
2025-12-20 | Additional Abstracts from the 2025 NMSG Meeting
Introduction: Limb-girdle muscular dystrophy 2E/R4 (LGMD2E/R4) is caused by pathogenetic variants in the beta-sarcoglycan (SGCB) gene leading to muscle loss.Bidridistrogene xeboparvovec, an adeno-associated virus vector that delivers the full-length SGCB transgene, has shown biologic efficacy and an acceptable safety profile.Objectives: To present VOYAGENE (SRP-9003-102; NCT05876780) 18-month data evaluating bidridistrogene xeboparvovec treatment in ambulatory and nonambulatory participants with LGMD2E/R4.Methods: Six participants (aged 17-29 years; 1 ambulatory and 5 nonambulatory; 2 females) received a single infusion of 7.41x10 13 vg/kg bidridistrogene xeboparvovec.Primary endpoints were treatment-emergent adverse events (TEAEs) and day 60 SGCB expression in muscle biopsy via immunofluorescence (IF) and Western blot (WB).Secondary endpoints were day 60 muscle vector genome copies, North Star Assessment for LGMD (NSAD), and Performance of Upper Limb (PUL) 2.0 scores by month 60.Other endpoints included changes in forced vital capacity (FVC), forced expiratory volume in one second (FEV 1 ), and creatine kinase (CK) levels through month 60.Results: No serious TEAEs, discontinuations, or deaths were noted.All participants had TEAEs; most were grade 1 (n=87/153) or 2 (n=63/153), with mostly mild/moderate treatment-related TEAEs (grade 1-2: 40/43; grade 3 [severe]: 3/43).At day 60, muscle biopsy showed increases in SGCB-positive fibers by IF and expression by WB; vector genome DNA was detected in myofibers in all participants.Over time NSAD, PUL 2.0, FVC, and FEV 1 remained stable and participants had reduced CK levels.Conclusions: These findings show partial restoration of SGCB expression after bidridistrogene xeboparvovec treatment in ambulatory and nonambulatory LGMD2E/R4 individuals.
2025-11-06 | Pharmacokinetic and Pharmacodynamic Evaluation of Bidridistrogene Xeboparvovec in an Aged Murine Model of Limb-Girdle Muscular Dystrophy Type 2E/R4.
Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is an ultra-rare autosomal recessive disorder caused by mutations in SGCB, the gene that encodes for β-sarcoglycan (SGCB), a component of the dystrophin-associated protein complex that stabilizes muscle fibers during contractions. Bidridistrogene xeboparvovec is an investigational adeno-associated virus-mediated gene transfer therapy designed to deliver a codon-optimized, full-length human SGCB and induce targeted expression of functional human SGCB protein. Interim safety and efficacy data from a clinical trial in patients with LGDM2E/R4 aged 4-15 years (NCT03652259) support further clinical development of bidridistrogene xeboparvovec. However, less is known about the effects of this agent in patients with more advanced LGMD2E/R4, who on average are older and heavier, which prompted their inclusion in studies VOYAGENE (NCT05876780, phase 1) and EMERGENE (NCT06246513, phase 3). In the preclinical study presented here, we delivered bidridistrogene xeboparvovec (0.185 × 1013 vg/kg, 0.37 × 1013 vg/kg, 0.74 × 1013 vg/kg, 1.85 × 1013 vg/kg, or 7.4 × 1013 vg/kg) to Sgcb-/- mice aged 27-42 weeks (n = 4 per dose) with age-matched saline-treated Sgcb-/- and C57BL/6J mice used as controls. Approximately 12 weeks after administration, we observed SGCB expression and found evidence of reduction in muscle fibrosis, reduction in muscle damage, and restoration of muscle force. Overall, a dose-dependent increase in vector exposure across tissue types was observed, with a nonlinear, exposure-dependent increase in both SGCB expression and functional improvement that reached saturation at 7.4 × 1013 vg/kg. Pharmacokinetic and pharmacodynamic analyses demonstrated a robust relationship between vector biodistribution, SGCB expression, and muscle force, further supporting clinical development of bidridistrogene xeboparvovec at the highest dose (7.4 × 1013 vg/kg), across a broad LGMD2E/R4 population and regardless of disease progression.
2025-05-13 | A prospective observational study assessing the functional disease progression of LGMDR4, betasarcoglycan-related limb girdle muscular dystrophy.
Limb-girdle muscular dystrophy (LGMD) R4, betasarcoglycanopathy, is a progressive muscle disease that frequently presents in childhood and results in loss of ambulation around 20 years of age. With interventional trials on the horizon it is essential to document functional disease progression using standardized performance outcome assessments (PerfO). We present a prospective longitudinal observational study of individuals recruited through both Nationwide Children's Hospital neuromuscular clinics and through outreach events held in an area with a high incidence of Founder variant (c.452C > G). PerfOs included the NorthStar Assessment for limb-girdle dystrophies (NSAD), Performance of Upper Limb (PUL), timed function tests, and spirometry, as appropriate. Forty-six individuals enrolled (aged 3-55 years) with 22 (55%) ambulant. Most PerfOs quantified change over time. We found heterogeneity of functional abilities at all ages. In our cohort, children's performance improved until around age 7, followed by a plateau until around 10-12 years. The ability to rise from the floor was the first milestone lost and was unable to be completed by anyone who took longer than 7.7 s on the 10-meter. Further, performance on select PerfOs were related to skills of functional independence, informing clinical care and data driven trial design. There is a great deal of functional heterogeneity. The selected PerfOs measured motor function and disease progression in individuals with LGMDR4, for the benefit of both data driven clinical management and clinical trial design.
2025-03-25 | Sarcoglycanopathies: From clinical diagnosis to new promising therapies
The sarcoglycanopathies are a severe form of limb girdle muscular dystrophy caused by mutations in the sarcoglycan genes SGCA, SGCB, SGCG, and SGCD, leading to reduced or absent expression of the alpha-, beta-, gamma-, and delta-sarcoglycan proteins respectively. Most patients develop a severe disease starting in the first decade of life that progresses quickly and eventually leads to a loss of ambulation before the age of 20. However, there is a marked heterogeneity in the prognosis, and several patients develop a milder phenotype. The factors correlating with disease progression are not completely known, but recent data suggest that remaining protein expression can be a key factor. The diagnosis is confirmed by genetic studies, which are sometimes not confirmative in the case of identifying variants of unknown significance or just one variant. New tools to understand the potential pathogenesis of missense variants have been developed; these are helping in the diagnosis of these diseases. Additionally, recent data on muscle MRI have revealed a characteristic pattern of involvement that can also support the diagnosis of the disease. In recent years, data coming from international collaborative studies have allowed an understanding of disease progression; however, this is only through retrospective data. There are no prospective studies collecting longitudinal data on skeletal and respiratory muscle function or cardiac structure and function progression over time which is hampering the development of new drugs in the field. Clinical trials with gene therapy are underway or are being designed in some of the subtypes of sarcoglycanopathies to advance therapeutic management.
proteins
2024-09-09 | Sarcoglycans are Enriched at the Neuromuscular Junction in a Nerve-Dependent Manner
Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. These diseases are caused by mutations in genes coding for one of the four sarcoglycan transmembrane proteins, which form the sarcoglycan complex (SGC). Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that enrichment of sarcoglycans within the NMJ occurs only after innervation, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans' participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.
2022-11-01 | PGC-1α in the myofibers regulates the balance between myogenic and adipogenic progenitors affecting muscle regeneration
Skeletal muscle repair is accomplished by satellite cells (MuSCs) in cooperation with interstitial stromal cells (ISCs), but the relationship between the function of these cells and the metabolic state of myofibers remains unclear. This study reports an altered proportion of MuSCs and ISCs (including adipogenesis-regulatory cells; Aregs) induced by the transgenic overexpression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) in the myofibers (MCK-PGC-1α mice). Although PGC-1α-driven increase of MuSCs does not accelerate muscle regeneration, myogenic progenitors isolated from MCK-PGC-1α mice and transplanted into intact and regenerating muscles are more prone to fuse with recipient myofibers than those derived from wild-type donors. Moreover, both young and aged MCK-PGC-1α animals exhibit reduced perilipin-positive areas when challenged with an adipogenic stimulus, demonstrating low propensity to accumulate adipocytes within the muscle. Overall, these results unveil that increased PGC-1α expression in the myofibers favors pro-myogenic and anti-adipogenic cell populations in the skeletal muscle.
2018-02-15 | The enzymatic processing of α-dystroglycan by MMP-2 is controlled by two anchoring sites distinct from the active site
Dystroglycan (DG) is a membrane receptor, belonging to the dystrophin-glycoprotein complex (DGC) and formed by two subunits, α-dystroglycan (α-DG) and β-dystroglycan (β -DG). The C-terminal domain of α-DG and the N-terminal extracellular domain of β -DG are connected, providing a link between the extracellular matrix and the cytosol. Under pathological conditions, such as cancer and muscular dystrophies, DG may be the target of metalloproteinases MMP-2 and MMP-9, contributing to disease progression. Previously, we reported that the C-terminal domain α-DG (483–628) domain is particularly susceptible to the catalytic activity of MMP-2; here we show that the α-DG 621–628 region is required to carry out its complete digestion, suggesting that this portion may represent a MMP-2 anchoring site. Following this observation, we synthesized an α-DG based-peptide, spanning the (613–651) C-terminal region. The analysis of the kinetic and thermodynamic parameters of the whole and the isolated catalytic domain of MMP-2 (cdMMP-2) has shown its inhibitory properties, indicating the presence of (at least) two binding sites for the peptide, both located within the catalytic domain, only one of the two being topologically distinct from the catalytic active groove. However, the different behavior between whole MMP-2 and cdMMP-2 envisages the occurrence of an additional binding site for the peptide on the hemopexin-like domain of MMP-2. Interestingly, mass spectrometry analysis has shown that α-DG (613–651) peptide is cleavable even though it is a very poor substrate of MMP-2, a feature that renders this molecule a promising template for developing a selective MMP-2 inhibitor.
2015-10-12 | Reengineering a transmembrane protein to treat muscular dystrophy using exon skipping
Exon skipping uses antisense oligonucleotides as a treatment for genetic diseases. The antisense oligonucleotides used for exon skipping are designed to bypass premature stop codons in the target RNA and restore reading frame disruption. Exon skipping is currently being tested in humans with dystrophin gene mutations who have Duchenne muscular dystrophy. For Duchenne muscular dystrophy, the rationale for exon skipping derived from observations in patients with naturally occurring dystrophin gene mutations that generated internally deleted but partially functional dystrophin proteins. We have now expanded the potential for exon skipping by testing whether an internal, in-frame truncation of a transmembrane protein γ-sarcoglycan is functional. We generated an internally truncated γ-sarcoglycan protein that we have termed Mini-Gamma by deleting a large portion of the extracellular domain. Mini-Gamma provided functional and pathological benefits to correct the loss of γ-sarcoglycan in a Drosophila model, in heterologous cell expression studies, and in transgenic mice lacking γ-sarcoglycan. We generated a cellular model of human muscle disease and showed that multiple exon skipping could be induced in RNA that encodes a mutant human γ-sarcoglycan. Since Mini-Gamma represents removal of 4 of the 7 coding exons in γ-sarcoglycan, this approach provides a viable strategy to treat the majority of patients with γ-sarcoglycan gene mutations.
2014-02-20 | Enhanced Ca2+ influx from STIM1–Orai1 induces muscle pathology in mouse models of muscular dystrophy
Muscular dystrophy is a progressive muscle wasting disease that is thought to be initiated by unregulated Ca2+ influx into myofibers leading to their death. Store-operated Ca2+ entry (SOCE) through sarcolemmal Ca2+ selective Orai1 channels in complex with STIM1 in the sarcoplasmic reticulum is one such potential disease mechanism for pathologic Ca2+ entry. Here, we generated a mouse model of STIM1 overexpression in skeletal muscle to determine whether this type of Ca2+ entry could induce muscular dystrophy. Myofibers from muscle-specific STIM1 transgenic mice showed a significant increase in SOCE in skeletal muscle, modeling an observed increase in the same current in dystrophic myofibers. Histological and biochemical analysis of STIM1 transgenic mice showed fulminant muscle disease characterized by myofiber necrosis, swollen mitochondria, infiltration of inflammatory cells, enhanced interstitial fibrosis and elevated serum creatine kinase levels. This dystrophic-like disease in STIM1 transgenic mice was abrogated by crossing in a transgene expressing a dominant-negative Orai1 (dnOrai1) mutant. The dnOrai1 transgene also significantly reduced the severity of muscular dystrophy in both mdx (dystrophin mutant mice) and δ-sarcoglycan-deficient (Sgcd−/−) mouse models of disease. Hence, Ca2+ influx across an unstable sarcolemma due to increased activity of a STIM1–Orai1 complex is a disease determinant in muscular dystrophy, and hence, SOCE represents a potential therapeutic target.
cell therapies
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
2019-05-09 | (Epi)genetic Modifications in Myogenic Stem Cells: From Novel Insights to Therapeutic Perspectives
The skeletal muscle is considered to be an ideal target for stem cell therapy as it has an inherent regenerative capacity. Upon injury, the satellite cells, muscle stem cells that reside under the basal lamina of the myofibres, start to differentiate in order to reconstitute the myofibres while maintaining the initial stem cell pool. In recent years, it has become more and more evident that epigenetic mechanisms such as histon modifications, DNA methylations and microRNA modulations play a pivatol role in this differentiation process. By understanding the mechanisms behind myogenesis, researchers are able to use this knowledge to enhance the differentiation and engraftment potential of different muscle stem cells. Besides manipulation on an epigenetic level, recent advances in the field of genome-engineering allow site-specific modifications in the genome of these stem cells. Combining epigenetic control of the stem cell fate with the ability to site-specifically correct mutations or add genes for further cell control, can increase the use of stem cells as treatment of muscular dystrophies drastically. In this review, we will discuss the advances that have been made in genome-engineering and the epigenetic regulation of muscle stem cells and how this knowledge can help to get stem cell therapy to its full potential.
2017-07-27 | Human dental pulp pluripotent-like stem cells promote wound healing and muscle regeneration
Dental pulp represents an easily accessible autologous source of adult stem cells. A subset of these cells, named dental pulp pluripotent-like stem cells (DPPSC), shows high plasticity and can undergo multiple population doublings, making DPPSC an appealing tool for tissue repair or maintenance.DPPSC were harvested from the dental pulp of third molars extracted from young patients. Growth factors released by DPPSC were analysed using antibody arrays. Cells were cultured in specific differentiation media and their endothelial, smooth and skeletal muscle differentiation potential was evaluated. The therapeutic potential of DPPSC was tested in a wound healing mouse model and in two genetic mouse models of muscular dystrophy (Scid/mdx and Sgcb-null Rag2-null γc-null).DPPSC secreted several growth factors involved in angiogenesis and extracellular matrix deposition and improved vascularisation in all three murine models. Moreover, DPPSC stimulated re-epithelialisation and ameliorated collagen deposition and organisation in healing wounds. In dystrophic mice, DPPSC engrafted in the skeletal muscle of both dystrophic murine models and showed integration in muscular fibres and vessels. In addition, DPPSC treatment resulted in reduced fibrosis and collagen content, larger cross-sectional area of type II fast-glycolytic fibres and infiltration of higher numbers of proangiogenic CD206+ macrophages.Overall, DPPSC represent a potential source of stem cells to enhance the wound healing process and slow down dystrophic muscle degeneration.
2015-03-09 | PW1/Peg3 expression regulates key properties that determine mesoangioblast stem cell competence
Abstract Mesoangioblasts are vessel-associated progenitor cells that show therapeutic promise for the treatment of muscular dystrophy. Mesoangioblasts have the ability to undergo skeletal muscle differentiation and cross the blood vessel wall regardless of the developmental stage at which they are isolated. Here we show that PW1/Peg3 is expressed at high levels in mesoangioblasts obtained from mouse, dog and human tissues and its level of expression correlates with their myogenic competence. Silencing PW1/Peg3 markedly inhibits myogenic potential of mesoangioblasts in vitro through MyoD degradation. Moreover, lack of PW1/Peg3 abrogates mesoangioblast ability to cross the vessel wall and to engraft into damaged myofibres through the modulation of the junctional adhesion molecule-A. We conclude that PW1/Peg3 function is essential for conferring proper mesoangioblast competence and that the determination of PW1/Peg3 levels in human mesoangioblasts may serve as a biomarker to identify the best donor populations for therapeutic application in muscular dystrophies.
2013-12-01 | A Special Population of Regulatory T Cells Potentiates Muscle Repair
Long recognized to be potent suppressors of immune responses, Foxp3+CD4+ regulatory T (Treg) cells are being rediscovered as regulators of nonimmunological processes. We describe a phenotypically and functionally distinct population of Treg cells that rapidly accumulated in the acutely injured skeletal muscle of mice, just as invading myeloid-lineage cells switched from a proinflammatory to a proregenerative state. A Treg population of similar phenotype accumulated in muscles of genetically dystrophic mice. Punctual depletion of Treg cells during the repair process prolonged the proinflammatory infiltrate and impaired muscle repair, while treatments that increased or decreased Treg activities diminished or enhanced (respectively) muscle damage in a dystrophy model. Muscle Treg cells expressed the growth factor Amphiregulin, which acted directly on muscle satellite cells in vitro and improved muscle repair in vivo. Thus, Treg cells and their products may provide new therapeutic opportunities for wound repair and muscular dystrophies.
small molecules
2025-01-08 | Efficacy of Cystic Fibrosis Transmembrane Regulator Corrector C17 in Beta-Sarcoglycanopathy-Assessment of Patient's Primary Myotubes.
Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is a rare disease that currently has no cure. It is caused by defects in the SGCB gene, mainly missense mutations, which cause the impairment of the sarcoglycan complex, membrane fragility, and progressive muscle degeneration. Here, we studied the fate of some β-sarcoglycan (β-SG) missense mutants, confirming that, like α-SG missense mutants, they are targeted for degradation through the ubiquitin-proteasome system. These data, collected using HEK-293 cells expressing either the I119F- or Y184C mutants of β-SG, were subsequently confirmed in primary myotubes derived from an LGMD2E/R4 patient carrying a homozygous I92T mutation. The knowledge that β-SG with an amino acid substitution shares a pathway of degradation with α-SG mutants, allowed us to explore the pharmacological approach successfully tested in LGMD2D/R3. Several CFTR correctors, particularly corrector C17, preserved β-SG mutants from degradation and promoted localization at the sarcolemma of the entire SG complex. The presence of the complex, despite containing a mutated subunit, improved sarcolemma integrity, as evidenced by the reduced creatine kinase release from myotubes under hypoosmotic stress. These results suggest that β-SG missense mutants undergo proteasomal degradation as α-SG mutants, and that CFTR correctors, particularly C17, may be used as a potential therapeutic option for recovering and stabilizing the SG complex in patients with sarcoglycanopathies.
2023-01-16 | Targeting ryanodine receptors to treat human diseases
This Review provides an update on ryanodine receptors (RyRs) and their role in human diseases of heart, muscle, and brain. Calcium (Ca2+) is a requisite second messenger in all living organisms. From C. elegans to mammals, Ca2+ is necessary for locomotion, bodily functions, and neural activity. However, too much of a good thing can be bad. Intracellular Ca2+ overload can result in loss of function and death. Intracellular Ca2+ release channels evolved to safely provide large, rapid Ca2+ signals without exposure to toxic extracellular Ca2+. RyRs are intracellular Ca2+ release channels present throughout the zoosphere. Over the past 35 years, our knowledge of RyRs has advanced to the level of atomic-resolution structures revealing their role in the mechanisms underlying the pathogenesis of human disorders of heart, muscle, and brain. Stress-induced RyR-mediated intracellular Ca2+ leak in the heart can promote heart failure and cardiac arrhythmias. In skeletal muscle, RyR1 leak contributes to muscle weakness in inherited myopathies, to age-related loss of muscle function and cancer-associated muscle weakness, and to impaired muscle function in muscular dystrophies, including Duchenne. In the brain, leaky RyR channels contribute to cognitive dysfunction in Alzheimer's disease, posttraumatic stress disorder, and Huntington's disease. Novel therapeutics targeting dysfunctional RyRs are showing promise.
2020-03-06 | Combined Use of CFTR Correctors in LGMD2D Myotubes Improves Sarcoglycan Complex Recovery
Sarcoglycanopathies are rare limb girdle muscular dystrophies, still incurable, even though symptomatic treatments may slow down the disease progression. Most of the disease-causing defects are missense mutations leading to a folding defective protein, promptly removed by the cell's quality control, even if possibly functional. Recently, we repurposed small molecules screened for cystic fibrosis as potential therapeutics in sarcoglycanopathy. Indeed, cystic fibrosis transmembrane regulator (CFTR) correctors successfully recovered the defective sarcoglycan-complex in vitro. Our aim was to test the combined administration of some CFTR correctors with C17, the most effective on sarcoglycans identified so far, and evaluate the stability of the rescued sarcoglycan-complex. We treated differentiated myogenic cells from both sarcoglycanopathy and healthy donors, evaluating the global rescue and the sarcolemma localization of the mutated protein, by biotinylation assays and western blot analyses. We observed the additive/synergistic action of some compounds, gathering the first ideas on possible mechanism/s of action. Our data also suggest that a defective α-sarcoglycan is competent for assembly into the complex that, if helped in cell traffic, can successfully reach the sarcolemma. In conclusion, our results strengthen the idea that CFTR correctors, acting probably as proteostasis modulators, have the potential to progress as therapeutics for sarcoglycanopathies caused by missense mutations.
2018-02-08 | Novel inhibitor candidates of TRPV2 prevent damage of dystrophic myocytes and ameliorate against dilated cardiomyopathy in a hamster model
// Yuko Iwata 1 , Yoshimi Katayama 2, 5 , Yasushi Okuno 3 and Shigeo Wakabayashi 4, 6 1 Departments of Molecular Physiology and Clinical Research, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan 2 Pharmacological Research Laboratories, Drug Safety Testing Center Co., Ltd., Higashimatsuyama, Saitama, Japan 3 Department of Clinical System Onco-Informatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan 4 Departments of Molecular Physiology and Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka, Japan 5 Present affiliation: Biological Research Laboratories, Nissan Chemical Industries, Ltd, Shiraoka, Saitama, Japan 6 Present affiliation: Department of Pharmocology, Osaka Medical Collage, Takatsuki, Osaka, Japan Correspondence to: Yuko Iwata, email: yukoiwat@ncvc.go.jp Keywords: cardiomyopathy; muscular dystrophy; Ca2+ influx; Ca2+-permeable channel; therapy; Gerotarget Received: January 26, 2018 Accepted: February 01, 2018 Epub: February 08, 2018 Published: March 06, 2018 ABSTRACT Transient receptor potential cation channel, subfamily V, member 2 (TRPV2) is a principal candidate for abnormal Ca 2+ -entry pathways, which is a potential target for therapy of muscular dystrophy and cardiomyopathy. Here, an in silico drug screening and the following cell-based screening to measure the TRPV2 activation were carried out in HEK293 cells expressing TRPV2 using lead compounds (tranilast or SKF96365) and off-patent drug stocks. We identified 4 chemical compounds containing amino-benzoyl groups and 1 compound (lumin) containing an ethylquinolinium group as candidate TRPV2 inhibitors. Three of these compounds inhibited Ca 2+ entry through both mouse and human TRPV2, with IC 50 of less than 10 μM, but had no apparent effect on other members of TRP family such as TRPV1 and TRPC1. Particularly, lumin inhibited agonist-induced TRPV2 channel activity at a low dose. These compounds inhibited abnormally increased Ca 2+ influx and prevented stretch-induced skeletal muscle damage in cultured myocytes from dystrophic hamsters (J2N-k). Further, they ameliorated cardiac dysfunction, and prevented disease progression in vivo in the same J2N-k hamsters developing dilated cardiomyopathy as well as muscular dystrophy. The identified compounds described here are available as experimental tools and represent potential treatments for patients with cardiomyopathy and muscular dystrophy.
2013-03-19 | Leaky ryanodine receptors in β-sarcoglycan deficient mice: a potential common defect in muscular dystrophy.
Disruption of the sarcolemma-associated dystrophin-glycoprotein complex underlies multiple forms of muscular dystrophy, including Duchenne muscular dystrophy and sarcoglycanopathies. A hallmark of these disorders is muscle weakness. In a murine model of Duchenne muscular dystrophy, mdx mice, cysteine-nitrosylation of the calcium release channel/ryanodine receptor type 1 (RyR1) on the skeletal muscle sarcoplasmic reticulum causes depletion of the stabilizing subunit calstabin1 (FKBP12) from the RyR1 macromolecular complex. This results in a sarcoplasmic reticular calcium leak via defective RyR1 channels. This pathological intracellular calcium leak contributes to reduced calcium release and decreased muscle force production. It is unknown whether RyR1 dysfunction occurs also in other muscular dystrophies. To test this we used a murine model of Limb-Girdle muscular dystrophy, deficient in β-sarcoglycan (Sgcb-/-). Skeletal muscle RyR1 from Sgcb-/- deficient mice were oxidized, nitrosylated, and depleted of the stabilizing subunit calstabin1, which was associated with increased open probability of the RyR1 channels. Sgcb-/- deficient mice exhibited decreased muscle specific force and calcium transients, and displayed reduced exercise capacity. Treating Sgcb-/- mice with the RyR stabilizing compound S107 improved muscle specific force, calcium transients, and exercise capacity. We have previously reported similar findings in mdx mice, a murine model of Duchenne muscular dystrophy. Our data suggest that leaky RyR1 channels may underlie multiple forms of muscular dystrophy linked to mutations in genes encoding components of the dystrophin-glycoprotein complex. A common underlying abnormality in calcium handling indicates that pharmacological targeting of dysfunctional RyR1 could be a novel therapeutic approach to improve muscle function in Limb-Girdle and Duchenne muscular dystrophies.
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2023-01-27 | Activated Oncostatin M signaling drives cancer-associated skeletal muscle wasting
Summary Progressive weakness and muscle loss are associated with multiple chronic conditions including muscular dystrophy and cancer. Cancer-associated cachexia, characterized by dramatic weight loss and fatigue, leads to reduced quality of life and poor survival. Inflammatory cytokines have been implicated in muscle atrophy, however, available anti-cytokine therapies failed to prevent muscle wasting in cancer patients. We previously reported that muscle-specific deletion of the Oncostatin M (OSM) receptor (OSMR) preserved muscle mass and function in tumor-bearing mice. Here, we show that OSM is a potent inducer of muscle atrophy. OSM triggers cellular atrophy in primary myotubes utilizing the JAK/STAT3 pathway. Identification of OSM targets by RNA sequencing revealed the induction of various muscle atrophy-related genes, including Atrogin1 . OSM overexpression in mice caused muscle wasting while the neutralization of circulating OSM protected from tumor-driven loss of muscle mass and function. Our results indicate that activated OSM/OSMR signaling drives muscle atrophy, and the therapeutic targeting of this pathway may be useful in preventing muscle wasting.
2022-08-29 | Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene
Limb-girdle muscular dystrophies (LGMD) are clinically and genetically heterogenous presentations displaying predominantly proximal muscle weakness due to the loss of skeletal muscle fibers. Beta-sarcoglycanopathy (LGMDR4) results from biallelic molecular defects in SGCB and features pediatric onset with limb-girdle involvement, often complicated by respiratory and heart dysfunction. Here we describe a patient who presented at the age of 12 years reporting high creatine kinase levels and onset of cramps after strenuous exercise. Instrumental investigations, including a muscle biopsy, pointed towards a diagnosis of beta-sarcoglycanopathy. NGS panel sequencing identified two variants in the SGCB gene, one of which (c.243+1548T>C) was found to promote the inclusion of a pseudoexon between exons 2 and 3 in the SGCB transcript. Interestingly, we detected the same genotype in a previously reported LGMDR4 patient, deceased more than twenty years ago, who had escaped molecular diagnosis so far. After the delivery of morpholino oligomers targeting the pseudoexon in patient-specific induced pluripotent stem cells, we observed the correction of the physiological splicing and partial restoration of protein levels. Our findings prompt the analysis of the c.243+1548T>C variant in suspected LGMDR4 patients, especially those harbouring monoallelic SGCB variants, and provide a further example of the efficacy of antisense technology for the correction of molecular defects resulting in splicing abnormalities.
2008-03-11 | A phase I/IItrial of MYO‐029 in adult subjects with muscular dystrophy
Myostatin is an endogenous negative regulator of muscle growth and a novel target for muscle diseases. We conducted a safety trial of a neutralizing antibody to myostatin, MYO-029, in adult muscular dystrophies (Becker muscular dystrophy, facioscapulohumeral dystrophy, and limb-girdle muscular dystrophy).This double-blind, placebo-controlled, multinational, randomized study included 116 subjects divided into sequential dose-escalation cohorts, each receiving MYO-029 or placebo (Cohort 1 at 1 mg/kg; Cohort 2 at 3 mg/kg; Cohort 3 at 10 mg/kg; Cohort 4 at 30 mg/kg). Safety and adverse events were assessed by reported signs and symptoms, as well as by physical examinations, laboratory results, echocardiograms, electrocardiograms, and in subjects with facioscapulohumeral dystrophy, funduscopic and audiometry examinations. Biological activity of MYO-029 was assessed through manual muscle testing, quantitative muscle testing, timed function tests, subject-reported outcomes, magnetic resonance imaging studies, dual-energy radiographic absorptiometry studies, and muscle biopsy.MYO-029 had good safety and tolerability with the exception of cutaneous hypersensitivity at the 10 and 30 mg/kg doses. There were no improvements noted in exploratory end points of muscle strength or function, but the study was not powered to look for efficacy. Importantly, bioactivity of MYO-029 was supported by a trend in a limited number of subjects toward increased muscle size using dual-energy radiographic absorptiometry and muscle histology.This trial supports the hypothesis that systemic administration of myostatin inhibitors provides an adequate safety margin for clinical studies. Further evaluation of more potent myostatin inhibitors for stimulating muscle growth in muscular dystrophy should be considered.
2006-07-05 | Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophy.
Myostatin (MSTN) is a muscle-specific secreted peptide that functions to limit muscle growth through an autocrine regulatory feedback loop. Loss of MSTN activity in cattle, mice, and humans leads to a profound phenotype of muscle overgrowth, associated with more and larger fibers and enhanced regenerative capacity. Deletion of MSTN in the mdx mouse model of Duchenne muscular dystrophy enhances muscle mass and reduces disease severity. In contrast, loss of MSTN activity in the dyW/dyW mouse model of laminin-deficient congenital muscular dystrophy, a much more severe and lethal disease model, does not improve all aspects of muscle pathology. Here we examined disease severity associated with myostatin (mstn-/-) deletion in mice nullizygous for delta-sarcoglycan (scgd-/-), a model of limb-girdle muscular dystrophy. Early loss of MSTN activity achieved either by monoclonal antibody administration or by gene deletion each improved muscle mass, regeneration, and reduced fibrosis in scgd-/- mice. However, antibody-mediated inhibition of MSTN in late-stage dystrophic scgd-/- mice did not improve disease. These findings suggest that MSTN inhibition may benefit muscular dystrophy when instituted early or if disease is relatively mild but that MSTN inhibition in severely affected or late-stage disease may be ineffective.
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Drug Discovery Landscape
2 orphan drug designations for Beta-sarcoglycan-related limb-girdle muscular dystrophy R4.
2 orphan drug designations for Beta-sarcoglycan-related limb-girdle muscular dystrophy R4.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
bidridistrogene xeboparvovec | gene therapies | FDA | Sarepta Therapeutics | |
Kifunensine | small molecules | EMA | — | Genethon |
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