RARE DISEASE
Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5
Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5
Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2C, Gamma-sarcoglycan-related LGMD R5, Gamma-sarcoglycanopathy, LGMD due to gamma-sarcoglycan deficiency, LGMD type 2C, LGMD2C, Limb-girdle muscular dystrophy due to gamma-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2C
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2C, Gamma-sarcoglycan-related LGMD R5, Gamma-sarcoglycanopathy, LGMD due to gamma-sarcoglycan deficiency, LGMD type 2C, LGMD2C, Limb-girdle muscular dystrophy due to gamma-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2C
Synonyms: Autosomal recessive limb-girdle muscular dystrophy type 2C, Gamma-sarcoglycan-related LGMD R5, Gamma-sarcoglycanopathy, LGMD due to gamma-sarcoglycan deficiency, LGMD type 2C, LGMD2C, Limb-girdle muscular dystrophy due to gamma-sarcoglycan deficiency, Limb-girdle muscular dystrophy type 2C
Drug discovery
4
drugs
With orphan designations
Overview
Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5 (LGMD R5) is an autosomal recessive disorder caused by SGCG gene mutations, disrupting γ-sarcoglycan in the dystrophin-associated protein complex. Childhood-onset progressive weakness affects pelvic/pectoral girdles, with calf hypertrophy, elevated CK levels, and Gowers sign. Cardiac involvement (e.g., cardiomyopathy) and respiratory decline are common. Disease progression leads to ambulation loss by adolescence and premature mortality from cardiopulmonary complications [1][2][5][8].
Therapies
Gene therapy trials: Systemic AAV-mediated SGCG delivery (e.g., SRP-9005, ATA-200) restores sarcoglycan complex, improves histopathology/function in preclinical models; Phase 1 trials ongoing [1][3][10][14].
Supportive care: Physiotherapy (contracture management), respiratory support (nocturnal ventilation), and cardiac monitoring (ECG/echocardiography) [8][16].
Categories: rare cardiac diseases, rare genetic diseases, rare neurological diseases, rare transplant-related disorders
Research Papers
89 drug discovery papers about Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
89 drug discovery papers about Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5, with 1 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2025-06-19 | 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 DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of 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 beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting 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 gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-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 protect 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.
2024-05-08 | The extracellular matrix differentially directs myoblast motility and differentiation in distinct forms of muscular dystrophy: Dystrophic matrices alter myoblast motility.
Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin- and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity.
2024-05-06 | Advanced therapeutic approaches in sarcoglycanopathies
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
2024-01-03 | The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Abstract Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
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.
2025-06-19 | 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 DGC result in numerous muscular dystrophies, the three-dimensional structure of the complex has remained elusive. Two recent elegant cryoEM structures of 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 beta-dystroglycan to the beta-, gamma- and delta-sarcoglycan trimer, supporting 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 gamma-sarcoglycanopathies enabling substitution of gamma-sarcoglycan by its homolog, zeta-sarcoglycan, leading to the structural integrity of the DGC and prevention of limb-girdle muscular dystrophy R5. Three-dimensional modeling reveals that zeta-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 protect 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.
2024-05-08 | The extracellular matrix differentially directs myoblast motility and differentiation in distinct forms of muscular dystrophy: Dystrophic matrices alter myoblast motility.
Extracellular matrix (ECM) pathologic remodeling underlies many disorders, including muscular dystrophy. Tissue decellularization removes cellular components while leaving behind ECM components. We generated "on-slide" decellularized tissue slices from genetically distinct dystrophic mouse models. The ECM of dystrophin- and sarcoglycan-deficient muscles had marked thrombospondin 4 deposition, while dysferlin-deficient muscle had excess decorin. Annexins A2 and A6 were present on all dystrophic decellularized ECMs, but annexin matrix deposition was excessive in dysferlin-deficient muscular dystrophy. Muscle-directed viral expression of annexin A6 resulted in annexin A6 in the ECM. C2C12 myoblasts seeded onto decellularized matrices displayed differential myoblast mobility and fusion. Dystrophin-deficient decellularized matrices inhibited myoblast mobility, while dysferlin-deficient decellularized matrices enhanced myoblast movement and differentiation. Myoblasts treated with recombinant annexin A6 increased mobility and fusion like that seen on dysferlin-deficient decellularized matrix and demonstrated upregulation of ECM and muscle cell differentiation genes. These findings demonstrate specific fibrotic signatures elicit effects on myoblast activity.
2024-05-06 | Advanced therapeutic approaches in sarcoglycanopathies
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
2024-01-03 | The MuSK-BMP pathway maintains myofiber size in slow muscle through regulation of Akt-mTOR signaling
Abstract Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
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
4 orphan drug designations for Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5.
4 orphan drug designations for Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
adeno-associated virus expressing the full-length, consensus human coding sequence of gamma-sarcoglycan (SGCG) | gene therapies | FDA | 2026-02-27 | — | Evolyra Therapeutics |
recombinant adeno-associated virus serotype rhesus 74 expressing the human gamma-sarcoglycan transgene under the control of a myosin heavy chain creatine kinase muscle-specific promoter (rAAVrh74.MHCK7.hSGCG) | gene therapies | FDA | 2025-06-25 | — | Sarepta Therapeutics, Inc. |
adeno-associated virus serotype 8 containing the human SGCG gene | gene therapies | FDA | 2024-11-04 | — | Atamyo Therapeutics |
Adeno-associated viral vector serotype 1 containing the human sarcoglycan gamma gene | gene therapies | EMA | 2004-10-21 | — | Genethon |
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