RARE DISEASE
Myofibrillar myopathy
Myofibrillar myopathy
Myofibrillar myopathy
Synonyms: MFM
Synonyms: MFM
Synonyms: MFM
Drug discovery
1
drug
With orphan designation
Overview
Myofibrillar myopathy (MFM) is a rare, genetically heterogeneous group of neuromuscular disorders characterized by progressive skeletal muscle weakness, cardiomyopathy, and pathological Z-disc disintegration with protein aggregates. Onset ranges from infancy to late adulthood, typically manifesting as distal or proximal weakness. Cardiac involvement (arrhythmias, cardiomyopathy) and respiratory insufficiency are major complications. Diagnosis relies on muscle biopsy showing desmin-positive aggregates and genetic testing (mutations in DES, MYOT, BAG3, and others) [1][9][16].
Burden
Progressive disability (30% require wheelchairs), high cardiovascular morbidity/mortality (60% pacemaker dependence), and respiratory failure. Lifespan may normalize with early cardiac/respiratory intervention, but quality of life is significantly impacted by chronic disability and care needs [1][6][19].
Therapies
Symptom-focused management:
- Physical therapy, orthotics, and mobility aids to preserve function.
- Cardiac surveillance (pacemakers, transplantation) and respiratory support.
- Experimental approaches: Metformin for BAG3-related MFM and investigational drugs (e.g., CDD-2107) targeting autophagy [3][8][13].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
149 drug discovery papers about Myofibrillar myopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
149 drug discovery papers about Myofibrillar myopathy, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-07-06 | Unmasking Supervillin : SVIL haploinsufficiency causes hypertrophic cardiomyopathy by impairing mechanotransduction and cellular energetics
Abstract Background Rare heterozygous loss-of-function (LoF) variants in SVIL , encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. Methods Using CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVIL Q255X/+ and homozygous SVIL Q255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. Results The Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVIL Q255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVIL Q255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVIL Q255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVIL Q255X/+ cells but did not rescue energetic compromise. Conclusions Pathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL -associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical Perspective What Is New? SVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. Heterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. Mavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. What Are the Clinical Implications? Our findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. These findings establish SVIL -associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM The persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL -associated cardiomyopathy.
2026-07-02 | AAV-Delivered RNAi Targeting Mutant LDB3 Prevents and Reverses Myofibrillar Myopathy through Mechanosignaling Restoration.
The autosomal dominant p.Ala165Val mutation in LIM Domain Binding Protein 3 (LDB3) causes myofibrillar myopathy marked by Z-disc disruption, accumulation of filamin-C (FLNc) and chaperone proteins, and progressive muscle weakness. We previously showed that this mutation interferes with the LDB3-protein kinase C alpha (PKCα)-FLNc mechanosensing axis and impairs chaperone-assisted selective autophagy (CASA), establishing a gain-of-function mechanism. In this study, we examined whether mutant allele-specific knockdown could reverse the disease or mitigate disease progression in-vivo. A single intramuscular-injection of an AAV9-delivered microRNA-based shRNA produced substantial knockdown of mutant Ldb3 transcripts and protein in Ldb3 Ala165Val/+ knock-in mice treated either before or after the onset of pathology. Treatment after disease onset reduced filamin-C and CASA protein aggregates and improved muscle strength, whereas early intervention prevented development of molecular and histological features of myopathy. Phosphoproteomic profiling further showed broad remodeling of dysregulated phosphorylation networks, including restoration of PKCα-responsive sites and normalization of altered sarcomeric and cytoskeletal signaling observed in Ldb3 Ala165Val/+ mice. These findings identify disruption of the LDB3-PKCα-FLNc mechanosensing pathway as a central disease driver and suggest that restoring this signaling axis may complement mutant allele-specific RNA interference (RNAi). Overall, our results support RNAi as a promising therapeutic strategy for dominant LDB3-related myofibrillar myopathy.
2026-06-26 | A Novel Variant in the Desmin Gene: Case Report
Desminopathies are rare myofibrillar myopathies caused by variants in the desmin (DES) gene on chromosome 2q35, encoding the protein desmin. These variants, typically autosomal dominant missense, result in diverse clinical phenotypes, including progressive skeletal myopathy and cardiac involvement. Over 180 pathogenic variants and 700 variants of uncertain significance have been reported. We describe a 46-year-old male with progressive distal and proximal muscle weakness since age 30, functional impairment, and intermittent dysphagia. There was no family history or respiratory involvement. Electromyography demonstrated a myopathic pattern, and muscle biopsy revealed desmin- positive aggregates. The patient had a prior syncopal episode with minor chronic electrocardiographic abnormalities, suggesting possible cardiac involvement. Whole exome sequencing identified a novel heterozygous DES variant, c.1327_1328delinsTT, p.(Lys443Leu). The combined clinical, electrophysiological, and histopathological findings strongly support the likely pathogenicity of the identified variant. This case expands the spectrum of DES variants and highlights the importance of multidisciplinary evaluation.
2026-05-15 | Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
2026-04-17 | Cure MFM13 and Drug Repurposing Strategies for Myofibrillar Myopathy Type 13
Myofibrillar Myopathy type 13 with Rimmed Vacuoles (MFM13), (OMIM#621078) is an ultra-rare disease caused by a frameshift mutation in the HSPB8 gene. This mutation produces an abnormal HSPB8 protein with an elongated C-terminal tail, leading to toxic gain-of-function, promoting protein aggregation and autophagy impartment with muscle weakness phenotype. Currently, there are no approved treatments, and awareness of the disease remains limited. To address this critical gap, Cure MFM13 was established, as the first and only charitable initiative dedicated exclusively to this disease. Our mission is to improve the lives of all individuals affected by MFM13 by accelerating therapeutic development, advocating for patients, and building a global and empowered community.
We are currently focused on drug repurposing screening. We have developed several cellular models, including patient-derived fibroblasts and iPSCs. Because selecting the most appropriate cell model is critical to repurposing project success, we conducted extensive research on the use of C2C12 murine myoblasts and primary human myoblasts in studies of autophagy and muscle-related diseases. In addition, we are generating multiple research tools for the scientific community. Since the mutant HSPB8 protein differs structurally from the wild-type form, we developed a mutation-specific antibody targeting the frameshift variant (c.515dupC). To further accelerate progress, we are developing mouse model which next will be under investigation at a Czech Centre for Phenogenomics (CCP) in preparation for future preclinical testing.
At this stage, key questions remain: What is the most appropriate model for drug repurposing, considering that MFM13 is a slow-progressing, adult-onset, autophagy and muscle-related disease? Which assays best show the efficacy of candidate small molecules? And strategically, where to find collaborators and where to look for additional funding?
2026-07-06 | Unmasking Supervillin : SVIL haploinsufficiency causes hypertrophic cardiomyopathy by impairing mechanotransduction and cellular energetics
Abstract Background Rare heterozygous loss-of-function (LoF) variants in SVIL , encoding the Z-disk and costameric protein supervillin, have recently been identified as a cause of hypertrophic cardiomyopathy (HCM). Although supervillin is implicated in actin-dependent mechanotransduction, the mechanisms linking SVIL deficiency to cardiomyopathy remain poorly understood. Homozygous LoF cause a novel skeletal Myofibrillar Myopathy-10 (MFM-10) while heterozygous LoF cause HCM without skeletal myopathy. In this study we use a human model system to disentangle the LoF pathomechanism of the scaffolding protein supervillin in cardiomyocytes and its clinical implications. Methods Using CRISPR/Cas-9 we engineered a representative pathogenic LoF variant Q255X into an isogenic induced pluripotent stem cell (iPSC) line creating the heterozygous SVIL Q255X/+ and homozygous SVIL Q255X/Q255X cell lines. These lines were differentiated into iPSC-derived cardiomyocytes (iPSC-CMs) and cellular phenotypes were assessed using bulk RNA-sequencing, LC-MS proteomics, electrophysiological and calcium handling analyses, contractility measurements, sarcomere organization analysis, Seahorse metabolic flux assay, and pharmacological intervention with mavacamten. Results The Q255X variant resulted in SVIL haploinsufficiency at both RNA and protein levels with no evidence of a truncated protein. Compared with isogenic controls, SVIL Q255X/+ iPSC-CMs demonstrated action potential shortening, calcium transient elongation, sarcomeric disorganization and hypertrophy, and impaired mitochondrial respiration. Multi-omic analyses of SVIL Q255X/+ iPSC-CMs showed a profile of cellular stress and inflammation, hypertrophic and pro-fibrotic signalling, and a pseudohypoxic state driven by decreased respiration and a HIF-induced glycolytic shift. These abnormalities were not present in SVIL Q255X/Q255X cardiomyocytes, consistent with a relatively limited cardiac phenotype reported in homozygous variant carriers. Mavacamten improved sarcomeric disorganization and hypertrophy in SVIL Q255X/+ cells but did not rescue energetic compromise. Conclusions Pathogenic heterozygous SVIL LoF produces a distinct cellular phenotype characterized by impaired mechanotransduction, mitochondrial dysfunction, and maladaptive metabolic remodelling that promotes hypertrophic and pro-fibrotic signalling. These findings define a mechanistic basis for SVIL -associated cardiomyopathy and identify metabolic dysfunction as a potential therapeutic target beyond sarcomere-directed therapy. Clinical Perspective What Is New? SVIL haploinsufficiency causes HCM through a mechanism distinct from canonical sarcomeric disease, characterized by impaired mechanotransduction, mitochondrial dysfunction, and pseudohypoxia-driven metabolic remodeling. Heterozygous SVIL loss of function produces a substantially more severe cardiomyocyte phenotype than homozygous loss of function, providing a mechanistic explanation for the predominance of cardiac disease in heterozygous variant carriers. Mavacamten improves sarcomeric organization but does not restore impaired mitochondrial respiration, demonstrating that energetic dysfunction persists despite sarcomere-directed therapy. What Are the Clinical Implications? Our findings give functional evidence to support SVIL as a clinically relevant HCM disease gene and its inclusion in clinical genetic testing panels. These findings establish SVIL -associated cardiomyopathy as a mechanistically distinct form of HCM and offer insight into the pathomechanism of Z-disk and costameric HCM The persistence of mitochondrial dysfunction despite myosin inhibition suggests that drugs targeting mitochondrial bioenergetics may be a therapeutic strategy in patients with SVIL -associated cardiomyopathy.
2026-07-02 | AAV-Delivered RNAi Targeting Mutant LDB3 Prevents and Reverses Myofibrillar Myopathy through Mechanosignaling Restoration.
The autosomal dominant p.Ala165Val mutation in LIM Domain Binding Protein 3 (LDB3) causes myofibrillar myopathy marked by Z-disc disruption, accumulation of filamin-C (FLNc) and chaperone proteins, and progressive muscle weakness. We previously showed that this mutation interferes with the LDB3-protein kinase C alpha (PKCα)-FLNc mechanosensing axis and impairs chaperone-assisted selective autophagy (CASA), establishing a gain-of-function mechanism. In this study, we examined whether mutant allele-specific knockdown could reverse the disease or mitigate disease progression in-vivo. A single intramuscular-injection of an AAV9-delivered microRNA-based shRNA produced substantial knockdown of mutant Ldb3 transcripts and protein in Ldb3 Ala165Val/+ knock-in mice treated either before or after the onset of pathology. Treatment after disease onset reduced filamin-C and CASA protein aggregates and improved muscle strength, whereas early intervention prevented development of molecular and histological features of myopathy. Phosphoproteomic profiling further showed broad remodeling of dysregulated phosphorylation networks, including restoration of PKCα-responsive sites and normalization of altered sarcomeric and cytoskeletal signaling observed in Ldb3 Ala165Val/+ mice. These findings identify disruption of the LDB3-PKCα-FLNc mechanosensing pathway as a central disease driver and suggest that restoring this signaling axis may complement mutant allele-specific RNA interference (RNAi). Overall, our results support RNAi as a promising therapeutic strategy for dominant LDB3-related myofibrillar myopathy.
2026-06-26 | A Novel Variant in the Desmin Gene: Case Report
Desminopathies are rare myofibrillar myopathies caused by variants in the desmin (DES) gene on chromosome 2q35, encoding the protein desmin. These variants, typically autosomal dominant missense, result in diverse clinical phenotypes, including progressive skeletal myopathy and cardiac involvement. Over 180 pathogenic variants and 700 variants of uncertain significance have been reported. We describe a 46-year-old male with progressive distal and proximal muscle weakness since age 30, functional impairment, and intermittent dysphagia. There was no family history or respiratory involvement. Electromyography demonstrated a myopathic pattern, and muscle biopsy revealed desmin- positive aggregates. The patient had a prior syncopal episode with minor chronic electrocardiographic abnormalities, suggesting possible cardiac involvement. Whole exome sequencing identified a novel heterozygous DES variant, c.1327_1328delinsTT, p.(Lys443Leu). The combined clinical, electrophysiological, and histopathological findings strongly support the likely pathogenicity of the identified variant. This case expands the spectrum of DES variants and highlights the importance of multidisciplinary evaluation.
2026-05-15 | Autophagy activation via BAG3 gene therapy improves phenotype in a mouse model of LGMD1A.
Myofibrillar myopathies (MFMs) are a group of protein aggregate diseases characterized by abnormal protein aggregations and myofibrillar disintegration. Myotilinopathy, also named MFM3 or limb-girdle muscular dystrophy type 1A (LGMD1A), is caused by myotilin mutations. Myotilin is degraded by the ubiquitin-proteasome system; however, when this pathway is overloaded under pathophysiological conditions, the protein quality control system leans on the autophagy-lysosome pathway (ALP) to mediate degradation of aggregates. BCL2-associated athanogene 3 (BAG3) protein facilitates aggresome formation and initiates ALP. In this study, we assessed our strategy of reducing the aggregate burden in muscle by overexpressing human BAG3 in TgT57I mice, a model for LGMD1A. Overexpression was achieved by systemic delivery of AAVrh74.tMCK.hBAG3, and outcome measures included functional, histological, and molecular studies. The hBAG3-treated cohort demonstrated increased rotarod duration, treadmill running distance, grip strength, and maximum tetanic response compared to the untreated cohort. Myotilin aggregate burden was significantly decreased, and autophagy levels were normalized in the treated group. As an adaptive response, hBAG3 normalized the endogenous Bag1/Bag3 ratio to that of 3-month-old TgT57I mice. This study provides evidence that our strategy of reducing the aggregate burden in muscle by overexpressing BAG3 may be used as a treatment for protein aggregate myopathies.
2026-04-17 | Cure MFM13 and Drug Repurposing Strategies for Myofibrillar Myopathy Type 13
Myofibrillar Myopathy type 13 with Rimmed Vacuoles (MFM13), (OMIM#621078) is an ultra-rare disease caused by a frameshift mutation in the HSPB8 gene. This mutation produces an abnormal HSPB8 protein with an elongated C-terminal tail, leading to toxic gain-of-function, promoting protein aggregation and autophagy impartment with muscle weakness phenotype. Currently, there are no approved treatments, and awareness of the disease remains limited. To address this critical gap, Cure MFM13 was established, as the first and only charitable initiative dedicated exclusively to this disease. Our mission is to improve the lives of all individuals affected by MFM13 by accelerating therapeutic development, advocating for patients, and building a global and empowered community.
We are currently focused on drug repurposing screening. We have developed several cellular models, including patient-derived fibroblasts and iPSCs. Because selecting the most appropriate cell model is critical to repurposing project success, we conducted extensive research on the use of C2C12 murine myoblasts and primary human myoblasts in studies of autophagy and muscle-related diseases. In addition, we are generating multiple research tools for the scientific community. Since the mutant HSPB8 protein differs structurally from the wild-type form, we developed a mutation-specific antibody targeting the frameshift variant (c.515dupC). To further accelerate progress, we are developing mouse model which next will be under investigation at a Czech Centre for Phenogenomics (CCP) in preparation for future preclinical testing.
At this stage, key questions remain: What is the most appropriate model for drug repurposing, considering that MFM13 is a slow-progressing, adult-onset, autophagy and muscle-related disease? Which assays best show the efficacy of candidate small molecules? And strategically, where to find collaborators and where to look for additional funding?
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
1 orphan drug designation for Myofibrillar myopathy.
1 orphan drug designation for Myofibrillar myopathy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Chaenomelis Fructus Extract | small molecules | FDA | 2023-11-29 | — | Centre for Chinese Herbal Medicine Drug Development Limited |
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