RARE DISEASE
Collagen VI-related congenital muscular dystrophy
Collagen VI-related congenital muscular dystrophy
Collagen VI-related congenital muscular dystrophy
Synonyms: COL6-RD
Synonyms: COL6-RD
Synonyms: COL6-RD
Drug discovery
1
drug
With orphan designation
Overview
Collagen VI-related congenital muscular dystrophy (COL6-CMD) is a spectrum of rare genetic neuromuscular disorders caused by mutations in COL6A1, COL6A2, or COL6A3 genes. These mutations disrupt collagen VI, a critical extracellular matrix protein, leading to progressive muscle weakness, proximal joint contractures, distal hyperlaxity, and respiratory insufficiency. The disease ranges from Ullrich congenital muscular dystrophy (severe, early-onset) to Bethlem myopathy (milder, later-onset). Diagnosis combines clinical evaluation, genetic testing, muscle imaging, and biopsy. No cure exists, but proactive respiratory, orthopedic, and rehabilitative care improves quality of life [1][2][8][17].
Burden
Categories: rare genetic diseases, rare neurological diseases
Research Papers
63 drug discovery papers about Collagen VI-related congenital muscular dystrophy, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
63 drug discovery papers about Collagen VI-related congenital muscular dystrophy, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-07-29 | Expanding the phenotypic spectrum of COL6-related diseases: Motor neuropathy-like and neuromyopathy associated with COL6A3 c.7447A>G.
Collagen VI is a key component of the extracellular matrix. Murine models suggest that it regulates Schwann cell differentiation, peripheral nerve myelination and regeneration after injury. Neuropathic findings in COL6-related dystrophies (COL6-RDs) have been rarely reported, often based on electromyography findings without nerve conduction abnormalities. We report 37 patients (1.5-79 years), from 32 different families, carrying the COL6A3-c.7447A>G variant, presenting with neuropathic/neuromyopathic findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients, whereas 27% exhibited proximo-distal involvement. Foot deformities were present in 32%; joint contractures were present in 83%, exclusively affecting lower limbs in 49%. At last evaluation, mild restrictive respiratory insufficiency was diagnosed in 1 patient and nocturnal hypoventilation requiring non-invasive ventilation in 2. Most patients (89%) remained ambulant at last assessment. Nerve conduction studies (n=29) revealed reduced lower-limb CMAP amplitudes in 79%. Needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). Muscle imaging (n=23) revealed a typical COL6-RD pattern in 48% (with severe distal lower limb atrophy in 65%), and isolated or predominant distal atrophy in 30%. Inheritance was autosomal recessive in all cases. The COL6A3-c.7447A>G variant was present in homozygosity in 24 (65%) and in compound heterozygosity with a second COL6A3 variant in 13 (35%), including 8 previously unreported. We report an expanding phenotypic spectrum associated with COL6-RD, underscoring its relevance in the diagnostic evaluation of distal motor neuropathy-like or neuromyopathic presentations.
2025-04-07 | Inter- and intra-familial phenotypic variability of autosomal dominant collagen VI related disorder.
Collagen VI-related disorder (COL6-RD) is an inherited neuromuscular disease characterized by a broad spectrum of phenotypes. Eight families with autosomal dominant COL6-RD were recruited. Clinical manifestations, laboratory findings, electrophysiological results, molecular analyses, and pathological outcomes of eight index patients and their affected family members were systematically collected and reviewed. Pathogenic variants were identified in four families in the COL6A1 gene, one family in the COL6A2 gene, and three families in the COL6A3 gene. Among the index patients, three were classified as moderate progressive Ullrich congenital muscular dystrophy (UCMD), four exhibited mild UCMD or Bethlem myopathy, and one was diagnosed with Bethlem myopathy. The phenotypic presentation was relatively consistent within four families. However, intra-familial phenotypic variability was observed in four families, encompassing a wide range of onset ages, patterns and degrees of muscle weakness, rates of contracture progression, severity of skin changes, and age at loss of ambulation. Inter- and intra-familial phenotypic variability is prevalent in autosomal dominant COL6-RDs. When predicting the clinical course and severity for patients, it is crucial to integrate a comprehensive set of information, including mutation sites and types, family history, and early presenting features.
2019-03-27 | Adiponectin in Myopathies
In skeletal muscle, adiponectin has varied and pleiotropic functions, ranging from metabolic, anti-inflammatory, insulin-sensitizing to regenerative roles. Despite the important functions exerted by adiponectin, the study of the hormone in myopathies is still marginal. Myopathies include inherited and non-inherited/acquired neuromuscular pathologies characterized by muscular degeneration and weakness. This review reports current knowledge about adiponectin in myopathies, regarding in particular the role of adiponectin in some hereditary myopathies (as Duchenne muscular dystrophy) and non-inherited/acquired myopathies (such as idiopathic inflammatory myopathies and fibromyalgia). These studies show that some myopathies are characterized by decreased concentration of plasma adiponectin and that hormone replenishment induces beneficial effects in the diseased muscles. Overall, these findings suggest that adiponectin could constitute a future new therapeutic approach for the improvement of the abnormalities caused by myopathies.
2013-10-11 | Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets
Ullrich congenital muscular dystrophy (UCMD), caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other congenital muscular dystrophies. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.
2005-09-23 | Decorin and biglycan expression is differentially altered in several muscular dystrophies
Biglycan and decorin are small extracellular proteoglycans that interact with cytokines, whose activity they may modulate, and with matrix proteins, particularly collagens. To better understand their role in muscle fibrosis, we investigated expression of decorin and biglycan transcripts and protein in muscle of several forms of muscular dystrophy, and also expression of perlecan, an extracellular proteoglycan unrelated to collagen deposition. In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-β1. We examined muscle biopsies from nine DMD patients, aged 2–8 years; 14 BMD (Becker muscular dystrophy) patients (nine aged 1–5 years; five aged 30–37 years); four MDC1A patients (aged 2–7 years); six dysferlin-deficient patients (aged 19–53 years) with mutation ascertained in two, and normal expression of proteins related to limb girdle muscular dystrophies in the others; 10 sarcoglycan-deficient patients: seven with α-sarcoglycan mutation, two with β-sarcoglycan mutation and one with γ-sarcoglycan mutation (five aged 8–15 years; five aged 26–43 years); and nine children (aged 1–6 years) and 12 adults (aged 16–61 years) suspected of neuromuscular disease, but who had normal muscle on biopsy. Biglycan mRNA levels varied in DMD and MDC1A depending on the quantitation method, but were upregulated in BMD, sarcoglycanopathies and dysferlinopathy. Decorin mRNA was significantly downregulated in DMD and MDC1A, whereas TGF-β1 was significantly upregulated. Decorin mRNA was normal in paediatric BMD, but upregulated in adult BMD, sarcoglycanopathies and dysferlinopathy. Perlecan transcript levels were similar to those of age-matched controls in all disease groups. By immunohistochemistry, decorin and biglycan were mainly localized in muscle connective tissue; their presence increased in relation to increased fibrosis in all dystrophic muscle. By visual inspection, decorin bands on immunoblot did not differ from those of age-matched controls in all patient groups. However, when the intensity of the bands was quantitated against vimentin and normalized against sarcomeric actin, in DMD and MDC1A the ratio of band intensities was significantly lower than in age-matched controls. Variations in the transcript and protein levels of these proteoglycans in different muscular dystrophies probably reflect the variable disruption of extracellular matrix organization that occurs in these diseases. The significantly lowered decorin levels in DMD and MDC1A may be related to the increased TGF-β1 levels, suggesting a therapeutic role of decorin in these severe dystrophies.
oligonucleotides
2025-04-03 | Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T.
Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.
2024-03-29 | The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy
Abstract Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1 , COL6A2 or COL6A3 . With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 causative variant to a Bethlem muscular dystrophy phenotype.
2024-03-22 | A humanized knock-in Col6a1 mouse recapitulates a deep-intronic splice-activating variant.
Abstract Antisense therapeutics such as splice-modulating antisense oligonucleotides (ASOs) are promising tools to treat diseases caused by splice-altering intronic variants. However, their testing in animal models is hampered by the generally poor sequence conservation of the intervening sequences between human and other species. Here we aimed to model in the mouse a recurrent, deep-intronic, splice-activating, COL6A1 variant, associated with a severe form of Collagen VI-related muscular dystrophies (COL6-RDs), for the purpose of testing human-ready antisense therapeutics in vivo . The variant, c.930+189C>T, creates a donor splice site and inserts a 72-nt-long pseudoexon, which, when translated, acts in a dominant-negative manner, but which can be skipped with ASOs. We created a unique humanized mouse allele (designated as “h”), in which a 1.9 kb of the mouse genomic region encoding the amino-terminus (N-) of the triple helical (TH) domain of collagen α1(VI) was swapped for the human orthologous sequence. In addition, we also created an allele that carries the c.930+189C>T variant on the same humanized knock-in sequence (designated as “h+189T”). We show that in both models, the human exons are spliced seamlessly with the mouse exons to generate a chimeric mouse-human collagen α1(VI) protein. In homozygous Col6a1 h+189T/ h+189T mice, the pseudoexon is expressed at levels comparable to those observed in heterozygous patients’ muscle biopsies. While Col6a1 h/h mice do not show any phenotype compared to wild-type animals, Col6a1 h/ h+189T and Col6a1 h+189T/ h+189T mice have smaller muscle masses and display grip strength deficits detectable as early as 4 weeks of age. The pathogenic h+189T humanized knock-in mouse allele thus recapitulates the pathogenic splicing defects seen in patients’ biopsies and allows testing of human-ready precision antisense therapeutics aimed at skipping the pseudoexon. Given that the COL6A1 N-TH region is a hot-spot for COL6-RD variants, the humanized knock-in mouse model can be utilized as a template to introduce other COL6A1 pathogenic variants. This unique humanized mouse model thus represents a valuable tool for the development of antisense therapeutics for COL6-RDs.
2019-03-21 | A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies
The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI–related dystrophy (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen α1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splice-modulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.
2017-10-01 | A common dominant-negative COL6A1 pseudo-exon insertion is skippable using splice-modulating oligonucleotides
Collagen VI-related dystrophies (COL6-RD) are a group of frequently severe, congenital-onset neuromuscular disorders with no effective treatment. Our group has recently identified a new, and unexpectedly common, de novo deep-intronic mutation in intron 11 of the collagen 6 alpha 1 (COL6A1) gene (c.930 + 189C > T), associated with severe clinical manifestations. This deep-intronic mutation activates the insertion of an in-frame pseudo-exon, which we validated using minigene assays. Using minigenes, we also showed residual wild-type splicing occurring on the mutant allele, likely explaining the low expression levels of pseudo-exon-containing transcripts in muscle tissue (26.0%) and in skin-derived fibroblast cultures (9.0%). Given the severe clinical phenotype despite low expression levels, and the fact that the pseudo-exon is inserted at the N-terminal end of the triple-helical domain, a location where mutations typically exert dominant-negative effect, we investigated the effect of the mutation on collagen VI assembly. Evidences from non-denaturing immunoblotting, cultured cells' matrix immunofluorescence, and rotary shadowing electron microscopy suggest a strong dominant-negative mechanism of action for the COL6A1 pseudo-exon. As pseudo-exon mutations are potential targets for exon skipping using splice-modulating antisense oligonucleotides (ASOs), we screened a series of phosphorothioate morpholino (PMO) and 2'O-methyl ASOs. In patients' skin-derived fibroblasts, treatment with pseudo-exon-internal PMOs effectively skipped the pseudo-exon, reducing its levels by 92.0% at the highest dose, and blunted the dominant-negative effect. Given that the COL6A1 intronic mutation appears to be one of the most common mutations in the collagen 6 genes and given its severe clinical consequences, our proof-of-principle demonstration of splice-modulating oligonucleotides to suppress the pseudo-exon paves the way for rapid clinical translation and establishes precedence for other dominantly acting splice-inducing mutations.
cell therapies
2022-06-15 | The Use of Autologous Blood Patch in Ullrich Muscular Dystrophy and Recurrent Pneumothorax
We present the case of a 19-year-old female with Ullrich congenital muscular dystrophy (UCMD1, a collagen VI defect) who developed a right-sided pneumothorax after choking on a piece of meat. She received two chest tubes (pigtails) that resolved the pneumothorax. She was discharged in stable condition, and a chest radiograph two weeks later showed total resolution of the pneumothorax. Two months after this episode, the patient presented with another small, right-sided pneumothorax that shortly progressed to extension throughout the right side of the chest. These pneumothoraces were treated with three different pigtails, but this intervention was ineffective. Providers chose to utilize an autologous blood patch, which is an injection of the patient's own blood instilled in the pleural cavity through a chest drain. The blood forms a clot and subsequently seals the lung tissues through inflammation. This technique was chosen because the patient had advanced neuromuscular weakness with chronic respiratory failure. Also, our patient was not a candidate for chemical or surgical pleurodesis due to the nature of the persistent pneumothorax and the underlying lung fibrosis and collagen defect. Subsequent reaccumulation of the pneumothorax led to a second blood patch procedure, which proved effective. The patient recovered and was discharged in stable condition with no further episodes of pneumothorax over the subsequent 14 months from the initial episode.
2021-11-23 | Systemic Supplementation of Collagen VI by Neonatal Transplantation of iPSC-Derived MSCs Improves Histological Phenotype and Function of Col6-Deficient Model Mice
Collagen VI is distributed in the interstitium and is secreted mainly by mesenchymal stromal cells (MSCs) in skeletal muscle. Mutations in COL6A1-3 genes cause a spectrum of COL6-related myopathies. In this study, we performed a systemic transplantation study of human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) into neonatal immunodeficient COL6-related myopathy model (Col6a1KO /NSG) mice to validate the therapeutic potential. Engraftment of the donor cells and the resulting rescued collagen VI were observed at the quadriceps and diaphragm after intraperitoneal iMSC transplantation. Transplanted mice showed improvement in pathophysiological characteristics compared with untreated Col6a1KO /NSG mice. In detail, higher muscle regeneration in the transplanted mice resulted in increased muscle weight and enlarged myofibers. Eight-week-old mice showed increased muscle force and performed better in the grip and rotarod tests. Overall, these findings support the concept that systemic iMSC transplantation can be a therapeutic option for COL6-related myopathies.
2020-08-12 | Congenital Muscular Dystrophy-Associated Inflammatory Chemokines Provide Axes for Effective Recruitment of Therapeutic Adult Stem Cell into Muscles
Abstract Background: Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness. The two most prevalent forms of CMD, collagen VI-related myopathies (COL6RM) and laminin a2 deficient CMD type 1A (MDC1A), are both caused by deficiency or dysfunction of extracellular matrix proteins. Previously, we showed that an intramuscular transplantation of human adipose-derived stem cells (ADSC) into the muscle of the Col6a1 -/- mice results in efficient stem cell engraftment, migration, long-term survival, and continuous production of the collagen VI protein, suggesting the feasibility of the systemic cellular therapy for COL6RM. In order for this therapeutic approach to work however, stem cells must be efficiently targeted to the entire body musculature. Thus, the main goal of this study is to test whether muscle homing of systemically transplanted ADSC can be enhanced by employing muscle-specific chemotactic signals originating from CMD-affected muscle tissue. Methods: Proteomic screens of chemotactic molecules were conducted in the skeletal muscles of COL6RM- and MDC1A-affected patients and CMD mouse models to define the inflammatory and immune activities, thus, providing potential markers of disease activity or treatment effect. Also using a pre-clinical animal model, recapitulating mild Ullrich congenital muscular dystrophy (UCMD), the therapeutic relevance of identified chemotactic pathways was investigated in vivo, providing a basis for future clinical investigations. Results: Comprehensive proteomic screens evaluating relevant human and mouse skeletal muscle biopsies offered chemotactic axes to enhance directional migration of systemically transplanted cells into CMD-affected muscles, including CCL5-CCR1/3/5, CCL2-CCR2, CXCL1/2-CXCR1,2 and CXCL7-CXCR2. Also, the specific populations of ADSC selected with an affinity for the chemokines being released by damaged muscle showed efficient migration to injured site and presented their therapeutic effect. Conclusions: Collectively, identified molecules provided insight into the mechanisms governing directional migration and intra-muscular trafficking of systemically infused stem cells, thus, permitting broad and effective application of the therapeutic adult stem cells for CMD treatment.
2014-02-12 | Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy
Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in stem cell research have raised the possibility that use of adult stem cells may provide dramatic new therapies for treatment of COL6 CMD. Here, we developed a procedure for isolation of human stem cells from the adipose layer of neonatal skin. The adipose-derived stem cells (ADSC) were examined for expression of ECM and related genes using gene expression array analysis. The therapeutic potential of ADSC was assessed after a single intramuscular transplantation in collagen VI-deficient mice. Analysis of primary cultures confirmed that established ADSC represent a morphologically homogenous population with phenotypic and functional features of adult mesenchymal stem cells. A comprehensive gene expression analysis showed that ADSC express a vast array of ECM genes. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for COL6 CMD treatment. Furthermore, we have found that a single intramuscular transplantation of ADSC into Col6a1 −/− Rag1 −/− mice under physiological and cardiotoxin-induced injury/regeneration conditions results in efficient engraftment and migration of stem cells within the skeletal muscle. Importantly, we showed that ADSC can survive long-term and continuously secrete the therapeutic collagen VI protein missing in the mutant mice. Overall, our findings suggest that stem cell therapy can potentially provide a new avenue for the treatment of COL6 CMD and other muscular disorders and injuries.
2013-06-27 | Faculty Opinions recommendation of Collagen VI regulates satellite cell self-renewal and muscle regeneration.
Adult muscle stem cells, or satellite cells have essential roles in homeostasis and regeneration of skeletal muscles. Satellite cells are located within a niche that includes myofibers and extracellular matrix. The function of specific extracellular matrix molecules in regulating SCs is poorly understood. Here, we show that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1(-/-) mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. Collagen VI null muscles display significant decrease of stiffness, which is able to compromise the in vitro and in vivo activity of wild-type satellite cells. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1(-/-) muscles are ameliorated and satellite cell defects rescued. Our findings establish a critical role for an extracellular matrix molecule in satellite cell self-renewal and open new venues for therapies of collagen VI-related muscle diseases. PMID: 23743995 Funding information This work was supported by: NIA NIH HHS, United States Grant ID: R01 AG023806 NIA NIH HHS, United States Grant ID: R37 AG023806 Medical Research Council, United Kingdom Grant ID: MR/J006785/1 NIAMS NIH HHS, United States Grant ID: R01 AR056849 NIAMS NIH HHS, United States Grant ID: R01 AR062185 NIH HHS, United States Grant ID: DP1 OD000392 NIA NIH HHS, United States Grant ID: P01 AG036695 Medical Research Council, United Kingdom Grant ID: MR/K000608/1 Telethon, Italy Grant ID: GGP10225 NIAMS NIH HHS, United States Grant ID: R01 AR56849 Telethon, Italy Grant ID: GGP11082 More Less keyboard_arrow_down
gene therapies
2025-03-12 | Nanomechanics of cell-derived matrices as a functional read-out in collagen VI-related congenital muscular dystrophies.
Changes in the mechanical properties of the extracellular matrix (ECM) are a hallmark of disease. Due to its relevance, several in vitro models have been developed for the ECM, including cell-derived matrices (CDMs). CDMs are decellularized natural ECMs assembled by cells that closely mimic the in vivo stromal fibre organization and molecular content. Here, we applied atomic force microscopy-force spectroscopy (AFM-FS) to evaluate the nanomechanical properties of CDMs obtained from patients diagnosed with collagen VI-related congenital muscular dystrophies (COL6-RDs). COL6-RDs are a set of neuromuscular conditions caused by pathogenic variants in any of the three major COL6 genes, which result in deficiency or dysfunction of the COL6 incorporated into the ECM of connective tissues. Current diagnosis includes the genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability, as no direct correlation exists between genotype and phenotype of COL6-RDs. We describe differences in the elastic modulus (E) among CDMs from patients with different clinical phenotypes, as well as the restoration of E in CDMs obtained from genetically edited cells. Results anticipate the potential of the nanomechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
2024-11-27 | Restored Collagen VI Microfilaments Network in the Extracellular Matrix of CRISPR-Edited Ullrich Congenital Muscular Dystrophy Fibroblasts.
Collagen VI is an essential component of the extracellular matrix (ECM) composed by α1, α2 and α3 chains and encoded by COL6A1, COL6A2 and COL6A3 genes. Dominant negative pathogenic variants in COL6A genes result in defects in collagen VI protein and are implicated in the pathogenesis of muscular diseases, including Ullrich congenital muscular dystrophy (UCMD). Here, we designed a CRISPR genome editing strategy to tackle a dominant heterozygous deletion c.824_838del in exon 9 of the COL6A1 gene, causing a lack of secreted collagen VI in a patient's dermal fibroblasts. The evaluation of efficiency and specificity of gene editing in treating patient's fibroblasts revealed the 32% efficiency of editing the mutated allele but negligible editing of the wild-type allele. CRISPR-treated UCMD skin fibroblasts rescued the secretion of collagen VI in the ECM, which restored the ultrastructure of the collagen VI microfibril network. By using normal melanocytes as surrogates of muscle cells, we found that collagen VI secreted by the corrected patient's skin fibroblasts recovered the anchorage to the cell surface, pointing to a functional improvement of the protein properties. These results support the application of the CRISPR editing approach to knock out COL6A1 mutated alleles and rescue the UCMD phenotype in patient-derived fibroblasts.
2024-09-18 | Cell-derived matrices mechanics as a functional read-out in Collagen VI-related Congenital Muscular Dystrophies
Collagen VI-related congenital muscular dystrophies (COL6-RDs) are a set of neuromuscular conditions caused by pathogenic variants found in any of the three COL6 genes. The phenotypic expression of the disease does not directly correlate with the genetic background producing an overlapping spectrum of clinical phenotypes that goes from the mild Bethlem myopathy (BM) to the severe Ulrich congenital muscular dystrophy (UCMD). Diagnosis includes genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability. The development of new tools able to identify phenotype traits can significantly contribute to the diagnosis and prognosis of COL6-RDs. Mutations occurring in COL6 genes result in deficiency or dysfunction of COL6 incorporated into the extracellular matrix (ECM) of connective tissues, affecting its fibrillar structure. Our research group has established personalized pre-clinical models of COL6-RDs based on cell-derived matrices (CDMs), which allowed the direct observation of the fibrillar organization of the ECM in samples derived from patients, and to compare features amongst different phenotypes. Here, we have characterized the mechanical properties of CDMs from patients using atomic force microscopy-based force spectroscopy (AFM-FS). We observed that the elastic modulus (E) varies with the phenotype, and that it correlates with COL6 organization in the CDMs. We additionally used AFM-FS to evaluate matrices derived from genetically edited cells, which resulted in E value restoration compared to control samples. Altogether, these results anticipate the potential of mechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
2024-03-22 | Allele-specific CRISPR/Cas9 editing inactivates a single nucleotide variant associated with collagen VI muscular dystrophy
The application of allele-specific gene editing tools can expand the therapeutic options for dominant genetic conditions, either via gene correction or via allelic gene inactivation in situations where haploinsufficiency is tolerated. Here, we used allele-targeted CRISPR/Cas9 guide RNAs (gRNAs) to introduce inactivating frameshifting indels at a single nucleotide variant in the COL6A1 gene (c.868G>A; G290R), a variant that acts as dominant negative and that is associated with a severe form of congenital muscular dystrophy. We expressed spCas9 along with allele-targeted gRNAs, without providing a repair template, in primary fibroblasts derived from four patients and one control subject. Amplicon deep-sequencing for two gRNAs tested showed that single nucleotide deletions accounted for the majority of indels introduced. While activity of the two gRNAs was greater at the G290R allele, both gRNAs were also active at the wild-type allele. To enhance allele-selectivity, we introduced deliberate additional mismatches to one gRNA. One of these optimized gRNAs showed minimal activity at the WT allele, while generating productive edits and improving collagen VI matrix in cultured patient fibroblasts. This study strengthens the potential of gene editing to treat dominant-negative disorders, but also underscores the challenges in achieving allele selectivity with gRNAs.
2023-08-05 | New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients
Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials.
other
2026-04-22 | Collagen VI–Related Myopathies: An Educational Overview of Molecular Pathogenesis, Variability of Clinical Presentations Spectrum, Diagnostic Approaches and Management Strategies
Collagen VI–related myopathies (COL6-RM) encompass a broad clinical spectrum of inherited neuromuscular disorders ranging from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy, caused by pathogenic variants in COL6A1, COL6A2, and COL6A3. The pathogenic disruptions in collagen VI compromise extracellular matrix stability, impair autophagic flux, promote mitochondrial permeability transition, and alter fibroblast–myofiber signaling. These disorders are characterized by proximal muscle weakness, joint contractures, distal hyperlaxity, and respiratory compromise. Advances in basic science have revealed that collagen VI deficiency disrupts extracellular matrix (ECM) integrity, impairs autophagy, induces mitochondrial dysfunction, and alters the myomatrix microenvironment, collectively driving progressive muscle degeneration. Diagnosis relies on a multimodal approach that integrates clinical assessment with muscle MRI, histopathology, and next-generation sequencing. Management remains largely supportive; however, emerging strategies, including autophagy enhancers, mitochondrial permeability transition pore (mPTP) inhibitors, extracellular matrix–targeting agents, and genebased therapies show promise for disease modification. Advances in molecular biology have reshaped the understanding of COL6-RM and opened new avenues for targeted treatment. Robust natural history studies and biomarker development are needed to accelerate translational progress. The objective is to synthesize current evidence regarding pathogenesis, clinical presentation, diagnostic modalities, and evolving therapeutic approaches in COL6-RM. This review integrates and synthesizes findings from molecular pathogenesis, diagnostic tools, clinical spectrum, imaging studies, and evolving management while highlighting future therapeutic directions with emphasis on recent mechanisms involving extracellular matrix dysfunction, autophagy impairment, mitochondrial dysregulation, and myomatrix remodeling.
2025-12-30 | Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential.
Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions.
2024-06-25 | Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Clinical Trials NCT01805024.
2022-01-06 | Ablation of collagen VI leads to the release of platelets with altered function.
Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders. We observed a moderate bleeding tendency in patients affected by collagen VI-related disorders and investigated the defects in platelet functionality, whose mechanisms are unknown. We demonstrated that megakaryocytes express collagen VI that is involved in the regulation of functional platelet production. By exploiting a collagen VI-null mouse model (Col6a1-/-), we found that collagen VI-null platelets display significantly increased susceptibility to activation and intracellular calcium signaling. Col6a1-/- megakaryocytes and platelets showed increased expression of stromal interaction molecule 1 (STIM1) and ORAI1, the components of store-operated calcium entry (SOCE), and activation of the mammalian target of rapamycin (mTOR) signaling pathway. In vivo mTOR inhibition by rapamycin reduced STIM1 and ORAI1 expression and calcium flows, resulting in a normalization of platelet susceptibility to activation. These defects were cell autonomous, because transplantation of lineage-negative bone marrow cells from Col6a1-/- mice into lethally irradiated wild-type animals showed the same alteration in SOCE and platelet activation seen in Col6a1-/- mice. Peripheral blood platelets of patients affected by collagen VI-related diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy, displayed increased expression of STIM1 and ORAI1 and were more prone to activation. Altogether, these data demonstrate the importance of collagen VI in the production of functional platelets by megakaryocytes in mouse models and in collagen VI-related diseases.
2017-12-15 | Transcriptome profiling identifies regulators of pathogenesis in collagen VI related muscular dystrophy
Objectives The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies and are characterized by distal joint laxity and a combination of distal and proximal joint contractures. Inheritance can be dominant negative (DN) or recessive depending on the type and location of the mutation. DN mutations allow incorporation of abnormal chains into secreted tetramers and are the most commonly identified mutation type in COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains and act recessively. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD individuals from controls. Methods RNA-Seq allows precise detection of all expressed transcripts in a sample and provides a tool for quantification of expression data on a genomic scale. We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and 5 null) and 6 controls. To better assess the transcriptional changes induced by abnormal collagen VI in the extracellular matrix (ECM); we compared transcriptional profiles from subjects with DN mutations and subjects with null mutations to transcriptional profiles from controls. Results Differentially expressed transcripts between COL6-RD and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples. Conclusions Differentially expressed genes identified here may help identify new targets for development of therapies and biomarkers to assess the efficacy of treatments.
proteins
2026-07-29 | Expanding the phenotypic spectrum of COL6-related diseases: Motor neuropathy-like and neuromyopathy associated with COL6A3 c.7447A>G.
Collagen VI is a key component of the extracellular matrix. Murine models suggest that it regulates Schwann cell differentiation, peripheral nerve myelination and regeneration after injury. Neuropathic findings in COL6-related dystrophies (COL6-RDs) have been rarely reported, often based on electromyography findings without nerve conduction abnormalities. We report 37 patients (1.5-79 years), from 32 different families, carrying the COL6A3-c.7447A>G variant, presenting with neuropathic/neuromyopathic findings. Most patients presented in the first decade of life with an abnormal gait and frequent falls (54%), delayed motor milestones (32%) and foot deformities (19%). Predominant distal weakness was present in 46% of patients, whereas 27% exhibited proximo-distal involvement. Foot deformities were present in 32%; joint contractures were present in 83%, exclusively affecting lower limbs in 49%. At last evaluation, mild restrictive respiratory insufficiency was diagnosed in 1 patient and nocturnal hypoventilation requiring non-invasive ventilation in 2. Most patients (89%) remained ambulant at last assessment. Nerve conduction studies (n=29) revealed reduced lower-limb CMAP amplitudes in 79%. Needle EMG (n=31) revealed chronic neurogenic-like features in 84% and mixed neuromyogenic features in 13%. Muscle biopsy (n=12) demonstrated features suggestive of neuropathic involvement in 4 (33%) and mixed neuropathic-myopathic features in 5 (42%). Muscle imaging (n=23) revealed a typical COL6-RD pattern in 48% (with severe distal lower limb atrophy in 65%), and isolated or predominant distal atrophy in 30%. Inheritance was autosomal recessive in all cases. The COL6A3-c.7447A>G variant was present in homozygosity in 24 (65%) and in compound heterozygosity with a second COL6A3 variant in 13 (35%), including 8 previously unreported. We report an expanding phenotypic spectrum associated with COL6-RD, underscoring its relevance in the diagnostic evaluation of distal motor neuropathy-like or neuromyopathic presentations.
2025-04-07 | Inter- and intra-familial phenotypic variability of autosomal dominant collagen VI related disorder.
Collagen VI-related disorder (COL6-RD) is an inherited neuromuscular disease characterized by a broad spectrum of phenotypes. Eight families with autosomal dominant COL6-RD were recruited. Clinical manifestations, laboratory findings, electrophysiological results, molecular analyses, and pathological outcomes of eight index patients and their affected family members were systematically collected and reviewed. Pathogenic variants were identified in four families in the COL6A1 gene, one family in the COL6A2 gene, and three families in the COL6A3 gene. Among the index patients, three were classified as moderate progressive Ullrich congenital muscular dystrophy (UCMD), four exhibited mild UCMD or Bethlem myopathy, and one was diagnosed with Bethlem myopathy. The phenotypic presentation was relatively consistent within four families. However, intra-familial phenotypic variability was observed in four families, encompassing a wide range of onset ages, patterns and degrees of muscle weakness, rates of contracture progression, severity of skin changes, and age at loss of ambulation. Inter- and intra-familial phenotypic variability is prevalent in autosomal dominant COL6-RDs. When predicting the clinical course and severity for patients, it is crucial to integrate a comprehensive set of information, including mutation sites and types, family history, and early presenting features.
2019-03-27 | Adiponectin in Myopathies
In skeletal muscle, adiponectin has varied and pleiotropic functions, ranging from metabolic, anti-inflammatory, insulin-sensitizing to regenerative roles. Despite the important functions exerted by adiponectin, the study of the hormone in myopathies is still marginal. Myopathies include inherited and non-inherited/acquired neuromuscular pathologies characterized by muscular degeneration and weakness. This review reports current knowledge about adiponectin in myopathies, regarding in particular the role of adiponectin in some hereditary myopathies (as Duchenne muscular dystrophy) and non-inherited/acquired myopathies (such as idiopathic inflammatory myopathies and fibromyalgia). These studies show that some myopathies are characterized by decreased concentration of plasma adiponectin and that hormone replenishment induces beneficial effects in the diseased muscles. Overall, these findings suggest that adiponectin could constitute a future new therapeutic approach for the improvement of the abnormalities caused by myopathies.
2013-10-11 | Gene Expression Profiling Identifies Molecular Pathways Associated with Collagen VI Deficiency and Provides Novel Therapeutic Targets
Ullrich congenital muscular dystrophy (UCMD), caused by collagen VI deficiency, is a common congenital muscular dystrophy. At present, the role of collagen VI in muscle and the mechanism of disease are not fully understood. To address this we have applied microarrays to analyse the transcriptome of UCMD muscle and compare it to healthy muscle and other muscular dystrophies. We identified 389 genes which are differentially regulated in UCMD relative to controls. In addition, there were 718 genes differentially expressed between UCMD and dystrophin deficient muscle. In contrast, only 29 genes were altered relative to other congenital muscular dystrophies. Changes in gene expression were confirmed by real-time PCR. The set of regulated genes was analysed by Gene Ontology, KEGG pathways and Ingenuity Pathway analysis to reveal the molecular functions and gene networks associated with collagen VI defects. The most significantly regulated pathways were those involved in muscle regeneration, extracellular matrix remodelling and inflammation. We characterised the immune response in UCMD biopsies as being mainly mediated via M2 macrophages and the complement pathway indicating that anti-inflammatory treatment may be beneficial to UCMD as for other dystrophies. We studied the immunolocalisation of ECM components and found that biglycan, a collagen VI interacting proteoglycan, was reduced in the basal lamina of UCMD patients. We propose that biglycan reduction is secondary to collagen VI loss and that it may be contributing towards UCMD pathophysiology. Consequently, strategies aimed at over-expressing biglycan and restore the link between the muscle cell surface and the extracellular matrix should be considered.
2005-09-23 | Decorin and biglycan expression is differentially altered in several muscular dystrophies
Biglycan and decorin are small extracellular proteoglycans that interact with cytokines, whose activity they may modulate, and with matrix proteins, particularly collagens. To better understand their role in muscle fibrosis, we investigated expression of decorin and biglycan transcripts and protein in muscle of several forms of muscular dystrophy, and also expression of perlecan, an extracellular proteoglycan unrelated to collagen deposition. In Duchenne muscular dystrophy (DMD) and LAMA2-mutated congenital muscular dystrophy (MDC1A) we also quantitated transcript levels of the profibrotic cytokine TGF-β1. We examined muscle biopsies from nine DMD patients, aged 2–8 years; 14 BMD (Becker muscular dystrophy) patients (nine aged 1–5 years; five aged 30–37 years); four MDC1A patients (aged 2–7 years); six dysferlin-deficient patients (aged 19–53 years) with mutation ascertained in two, and normal expression of proteins related to limb girdle muscular dystrophies in the others; 10 sarcoglycan-deficient patients: seven with α-sarcoglycan mutation, two with β-sarcoglycan mutation and one with γ-sarcoglycan mutation (five aged 8–15 years; five aged 26–43 years); and nine children (aged 1–6 years) and 12 adults (aged 16–61 years) suspected of neuromuscular disease, but who had normal muscle on biopsy. Biglycan mRNA levels varied in DMD and MDC1A depending on the quantitation method, but were upregulated in BMD, sarcoglycanopathies and dysferlinopathy. Decorin mRNA was significantly downregulated in DMD and MDC1A, whereas TGF-β1 was significantly upregulated. Decorin mRNA was normal in paediatric BMD, but upregulated in adult BMD, sarcoglycanopathies and dysferlinopathy. Perlecan transcript levels were similar to those of age-matched controls in all disease groups. By immunohistochemistry, decorin and biglycan were mainly localized in muscle connective tissue; their presence increased in relation to increased fibrosis in all dystrophic muscle. By visual inspection, decorin bands on immunoblot did not differ from those of age-matched controls in all patient groups. However, when the intensity of the bands was quantitated against vimentin and normalized against sarcomeric actin, in DMD and MDC1A the ratio of band intensities was significantly lower than in age-matched controls. Variations in the transcript and protein levels of these proteoglycans in different muscular dystrophies probably reflect the variable disruption of extracellular matrix organization that occurs in these diseases. The significantly lowered decorin levels in DMD and MDC1A may be related to the increased TGF-β1 levels, suggesting a therapeutic role of decorin in these severe dystrophies.
oligonucleotides
2025-04-03 | Characterization of severe COL6-related dystrophy due to the recurrent variant COL6A1 c.930+189C>T.
Collagen VI-related dystrophies manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterized by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognized later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and muscle pathology features highly suggestive of collagen VI-related dystrophy, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA sequencing and whole-genome sequencing, we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterized an international cohort of 44 patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterized by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Partial amelioration of the disease phenotype in this individual provides a strong rationale for the development of our pseudoexon skipping therapy to successfully suppress the pseudoexon insertion, resulting in normal COL6A1 transcripts. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 variant.
2024-03-29 | The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy
Abstract Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1 , COL6A2 or COL6A3 . With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 causative variant to a Bethlem muscular dystrophy phenotype.
2024-03-22 | A humanized knock-in Col6a1 mouse recapitulates a deep-intronic splice-activating variant.
Abstract Antisense therapeutics such as splice-modulating antisense oligonucleotides (ASOs) are promising tools to treat diseases caused by splice-altering intronic variants. However, their testing in animal models is hampered by the generally poor sequence conservation of the intervening sequences between human and other species. Here we aimed to model in the mouse a recurrent, deep-intronic, splice-activating, COL6A1 variant, associated with a severe form of Collagen VI-related muscular dystrophies (COL6-RDs), for the purpose of testing human-ready antisense therapeutics in vivo . The variant, c.930+189C>T, creates a donor splice site and inserts a 72-nt-long pseudoexon, which, when translated, acts in a dominant-negative manner, but which can be skipped with ASOs. We created a unique humanized mouse allele (designated as “h”), in which a 1.9 kb of the mouse genomic region encoding the amino-terminus (N-) of the triple helical (TH) domain of collagen α1(VI) was swapped for the human orthologous sequence. In addition, we also created an allele that carries the c.930+189C>T variant on the same humanized knock-in sequence (designated as “h+189T”). We show that in both models, the human exons are spliced seamlessly with the mouse exons to generate a chimeric mouse-human collagen α1(VI) protein. In homozygous Col6a1 h+189T/ h+189T mice, the pseudoexon is expressed at levels comparable to those observed in heterozygous patients’ muscle biopsies. While Col6a1 h/h mice do not show any phenotype compared to wild-type animals, Col6a1 h/ h+189T and Col6a1 h+189T/ h+189T mice have smaller muscle masses and display grip strength deficits detectable as early as 4 weeks of age. The pathogenic h+189T humanized knock-in mouse allele thus recapitulates the pathogenic splicing defects seen in patients’ biopsies and allows testing of human-ready precision antisense therapeutics aimed at skipping the pseudoexon. Given that the COL6A1 N-TH region is a hot-spot for COL6-RD variants, the humanized knock-in mouse model can be utilized as a template to introduce other COL6A1 pathogenic variants. This unique humanized mouse model thus represents a valuable tool for the development of antisense therapeutics for COL6-RDs.
2019-03-21 | A recurrent COL6A1 pseudoexon insertion causes muscular dystrophy and is effectively targeted by splice-correction therapies
The clinical application of advanced next-generation sequencing technologies is increasingly uncovering novel classes of mutations that may serve as potential targets for precision medicine therapeutics. Here, we show that a deep intronic splice defect in the COL6A1 gene, originally discovered by applying muscle RNA sequencing in patients with clinical findings of collagen VI–related dystrophy (COL6-RD), inserts an in-frame pseudoexon into COL6A1 mRNA, encodes a mutant collagen α1(VI) protein that exerts a dominant-negative effect on collagen VI matrix assembly, and provides a unique opportunity for splice-correction approaches aimed at restoring normal gene expression. Using splice-modulating antisense oligomers, we efficiently skipped the pseudoexon in patient-derived fibroblast cultures and restored a wild-type matrix. Similarly, we used CRISPR/Cas9 to precisely delete an intronic sequence containing the pseudoexon and efficiently abolish its inclusion while preserving wild-type splicing. Considering that this splice defect is emerging as one of the single most frequent mutations in COL6-RD, the design of specific and effective splice-correction therapies offers a promising path for clinical translation.
2017-10-01 | A common dominant-negative COL6A1 pseudo-exon insertion is skippable using splice-modulating oligonucleotides
Collagen VI-related dystrophies (COL6-RD) are a group of frequently severe, congenital-onset neuromuscular disorders with no effective treatment. Our group has recently identified a new, and unexpectedly common, de novo deep-intronic mutation in intron 11 of the collagen 6 alpha 1 (COL6A1) gene (c.930 + 189C > T), associated with severe clinical manifestations. This deep-intronic mutation activates the insertion of an in-frame pseudo-exon, which we validated using minigene assays. Using minigenes, we also showed residual wild-type splicing occurring on the mutant allele, likely explaining the low expression levels of pseudo-exon-containing transcripts in muscle tissue (26.0%) and in skin-derived fibroblast cultures (9.0%). Given the severe clinical phenotype despite low expression levels, and the fact that the pseudo-exon is inserted at the N-terminal end of the triple-helical domain, a location where mutations typically exert dominant-negative effect, we investigated the effect of the mutation on collagen VI assembly. Evidences from non-denaturing immunoblotting, cultured cells' matrix immunofluorescence, and rotary shadowing electron microscopy suggest a strong dominant-negative mechanism of action for the COL6A1 pseudo-exon. As pseudo-exon mutations are potential targets for exon skipping using splice-modulating antisense oligonucleotides (ASOs), we screened a series of phosphorothioate morpholino (PMO) and 2'O-methyl ASOs. In patients' skin-derived fibroblasts, treatment with pseudo-exon-internal PMOs effectively skipped the pseudo-exon, reducing its levels by 92.0% at the highest dose, and blunted the dominant-negative effect. Given that the COL6A1 intronic mutation appears to be one of the most common mutations in the collagen 6 genes and given its severe clinical consequences, our proof-of-principle demonstration of splice-modulating oligonucleotides to suppress the pseudo-exon paves the way for rapid clinical translation and establishes precedence for other dominantly acting splice-inducing mutations.
cell therapies
2022-06-15 | The Use of Autologous Blood Patch in Ullrich Muscular Dystrophy and Recurrent Pneumothorax
We present the case of a 19-year-old female with Ullrich congenital muscular dystrophy (UCMD1, a collagen VI defect) who developed a right-sided pneumothorax after choking on a piece of meat. She received two chest tubes (pigtails) that resolved the pneumothorax. She was discharged in stable condition, and a chest radiograph two weeks later showed total resolution of the pneumothorax. Two months after this episode, the patient presented with another small, right-sided pneumothorax that shortly progressed to extension throughout the right side of the chest. These pneumothoraces were treated with three different pigtails, but this intervention was ineffective. Providers chose to utilize an autologous blood patch, which is an injection of the patient's own blood instilled in the pleural cavity through a chest drain. The blood forms a clot and subsequently seals the lung tissues through inflammation. This technique was chosen because the patient had advanced neuromuscular weakness with chronic respiratory failure. Also, our patient was not a candidate for chemical or surgical pleurodesis due to the nature of the persistent pneumothorax and the underlying lung fibrosis and collagen defect. Subsequent reaccumulation of the pneumothorax led to a second blood patch procedure, which proved effective. The patient recovered and was discharged in stable condition with no further episodes of pneumothorax over the subsequent 14 months from the initial episode.
2021-11-23 | Systemic Supplementation of Collagen VI by Neonatal Transplantation of iPSC-Derived MSCs Improves Histological Phenotype and Function of Col6-Deficient Model Mice
Collagen VI is distributed in the interstitium and is secreted mainly by mesenchymal stromal cells (MSCs) in skeletal muscle. Mutations in COL6A1-3 genes cause a spectrum of COL6-related myopathies. In this study, we performed a systemic transplantation study of human-induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) into neonatal immunodeficient COL6-related myopathy model (Col6a1KO /NSG) mice to validate the therapeutic potential. Engraftment of the donor cells and the resulting rescued collagen VI were observed at the quadriceps and diaphragm after intraperitoneal iMSC transplantation. Transplanted mice showed improvement in pathophysiological characteristics compared with untreated Col6a1KO /NSG mice. In detail, higher muscle regeneration in the transplanted mice resulted in increased muscle weight and enlarged myofibers. Eight-week-old mice showed increased muscle force and performed better in the grip and rotarod tests. Overall, these findings support the concept that systemic iMSC transplantation can be a therapeutic option for COL6-related myopathies.
2020-08-12 | Congenital Muscular Dystrophy-Associated Inflammatory Chemokines Provide Axes for Effective Recruitment of Therapeutic Adult Stem Cell into Muscles
Abstract Background: Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness. The two most prevalent forms of CMD, collagen VI-related myopathies (COL6RM) and laminin a2 deficient CMD type 1A (MDC1A), are both caused by deficiency or dysfunction of extracellular matrix proteins. Previously, we showed that an intramuscular transplantation of human adipose-derived stem cells (ADSC) into the muscle of the Col6a1 -/- mice results in efficient stem cell engraftment, migration, long-term survival, and continuous production of the collagen VI protein, suggesting the feasibility of the systemic cellular therapy for COL6RM. In order for this therapeutic approach to work however, stem cells must be efficiently targeted to the entire body musculature. Thus, the main goal of this study is to test whether muscle homing of systemically transplanted ADSC can be enhanced by employing muscle-specific chemotactic signals originating from CMD-affected muscle tissue. Methods: Proteomic screens of chemotactic molecules were conducted in the skeletal muscles of COL6RM- and MDC1A-affected patients and CMD mouse models to define the inflammatory and immune activities, thus, providing potential markers of disease activity or treatment effect. Also using a pre-clinical animal model, recapitulating mild Ullrich congenital muscular dystrophy (UCMD), the therapeutic relevance of identified chemotactic pathways was investigated in vivo, providing a basis for future clinical investigations. Results: Comprehensive proteomic screens evaluating relevant human and mouse skeletal muscle biopsies offered chemotactic axes to enhance directional migration of systemically transplanted cells into CMD-affected muscles, including CCL5-CCR1/3/5, CCL2-CCR2, CXCL1/2-CXCR1,2 and CXCL7-CXCR2. Also, the specific populations of ADSC selected with an affinity for the chemokines being released by damaged muscle showed efficient migration to injured site and presented their therapeutic effect. Conclusions: Collectively, identified molecules provided insight into the mechanisms governing directional migration and intra-muscular trafficking of systemically infused stem cells, thus, permitting broad and effective application of the therapeutic adult stem cells for CMD treatment.
2014-02-12 | Human adipose-derived stem cell transplantation as a potential therapy for collagen VI-related congenital muscular dystrophy
Congenital muscular dystrophies (CMD) are a clinically and genetically heterogeneous group of neuromuscular disorders characterized by muscle weakness within the first two years of life. Collagen VI-related muscle disorders have recently emerged as one of the most common types of CMD. COL6 CMD is caused by deficiency and/or dysfunction of extracellular matrix (ECM) protein collagen VI. Currently, there is no specific treatment for this disabling and life-threatening disease. The primary cellular targets for collagen VI CMD therapy are fibroblasts in muscle, tendon and skin, as opposed to muscle cells for other types of muscular dystrophies. However, recent advances in stem cell research have raised the possibility that use of adult stem cells may provide dramatic new therapies for treatment of COL6 CMD. Here, we developed a procedure for isolation of human stem cells from the adipose layer of neonatal skin. The adipose-derived stem cells (ADSC) were examined for expression of ECM and related genes using gene expression array analysis. The therapeutic potential of ADSC was assessed after a single intramuscular transplantation in collagen VI-deficient mice. Analysis of primary cultures confirmed that established ADSC represent a morphologically homogenous population with phenotypic and functional features of adult mesenchymal stem cells. A comprehensive gene expression analysis showed that ADSC express a vast array of ECM genes. Importantly, it was observed that ADSC synthesize and secrete all three collagen VI chains, suggesting suitability of ADSC for COL6 CMD treatment. Furthermore, we have found that a single intramuscular transplantation of ADSC into Col6a1 −/− Rag1 −/− mice under physiological and cardiotoxin-induced injury/regeneration conditions results in efficient engraftment and migration of stem cells within the skeletal muscle. Importantly, we showed that ADSC can survive long-term and continuously secrete the therapeutic collagen VI protein missing in the mutant mice. Overall, our findings suggest that stem cell therapy can potentially provide a new avenue for the treatment of COL6 CMD and other muscular disorders and injuries.
2013-06-27 | Faculty Opinions recommendation of Collagen VI regulates satellite cell self-renewal and muscle regeneration.
Adult muscle stem cells, or satellite cells have essential roles in homeostasis and regeneration of skeletal muscles. Satellite cells are located within a niche that includes myofibers and extracellular matrix. The function of specific extracellular matrix molecules in regulating SCs is poorly understood. Here, we show that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1(-/-) mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. Collagen VI null muscles display significant decrease of stiffness, which is able to compromise the in vitro and in vivo activity of wild-type satellite cells. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1(-/-) muscles are ameliorated and satellite cell defects rescued. Our findings establish a critical role for an extracellular matrix molecule in satellite cell self-renewal and open new venues for therapies of collagen VI-related muscle diseases. PMID: 23743995 Funding information This work was supported by: NIA NIH HHS, United States Grant ID: R01 AG023806 NIA NIH HHS, United States Grant ID: R37 AG023806 Medical Research Council, United Kingdom Grant ID: MR/J006785/1 NIAMS NIH HHS, United States Grant ID: R01 AR056849 NIAMS NIH HHS, United States Grant ID: R01 AR062185 NIH HHS, United States Grant ID: DP1 OD000392 NIA NIH HHS, United States Grant ID: P01 AG036695 Medical Research Council, United Kingdom Grant ID: MR/K000608/1 Telethon, Italy Grant ID: GGP10225 NIAMS NIH HHS, United States Grant ID: R01 AR56849 Telethon, Italy Grant ID: GGP11082 More Less keyboard_arrow_down
gene therapies
2025-03-12 | Nanomechanics of cell-derived matrices as a functional read-out in collagen VI-related congenital muscular dystrophies.
Changes in the mechanical properties of the extracellular matrix (ECM) are a hallmark of disease. Due to its relevance, several in vitro models have been developed for the ECM, including cell-derived matrices (CDMs). CDMs are decellularized natural ECMs assembled by cells that closely mimic the in vivo stromal fibre organization and molecular content. Here, we applied atomic force microscopy-force spectroscopy (AFM-FS) to evaluate the nanomechanical properties of CDMs obtained from patients diagnosed with collagen VI-related congenital muscular dystrophies (COL6-RDs). COL6-RDs are a set of neuromuscular conditions caused by pathogenic variants in any of the three major COL6 genes, which result in deficiency or dysfunction of the COL6 incorporated into the ECM of connective tissues. Current diagnosis includes the genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability, as no direct correlation exists between genotype and phenotype of COL6-RDs. We describe differences in the elastic modulus (E) among CDMs from patients with different clinical phenotypes, as well as the restoration of E in CDMs obtained from genetically edited cells. Results anticipate the potential of the nanomechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
2024-11-27 | Restored Collagen VI Microfilaments Network in the Extracellular Matrix of CRISPR-Edited Ullrich Congenital Muscular Dystrophy Fibroblasts.
Collagen VI is an essential component of the extracellular matrix (ECM) composed by α1, α2 and α3 chains and encoded by COL6A1, COL6A2 and COL6A3 genes. Dominant negative pathogenic variants in COL6A genes result in defects in collagen VI protein and are implicated in the pathogenesis of muscular diseases, including Ullrich congenital muscular dystrophy (UCMD). Here, we designed a CRISPR genome editing strategy to tackle a dominant heterozygous deletion c.824_838del in exon 9 of the COL6A1 gene, causing a lack of secreted collagen VI in a patient's dermal fibroblasts. The evaluation of efficiency and specificity of gene editing in treating patient's fibroblasts revealed the 32% efficiency of editing the mutated allele but negligible editing of the wild-type allele. CRISPR-treated UCMD skin fibroblasts rescued the secretion of collagen VI in the ECM, which restored the ultrastructure of the collagen VI microfibril network. By using normal melanocytes as surrogates of muscle cells, we found that collagen VI secreted by the corrected patient's skin fibroblasts recovered the anchorage to the cell surface, pointing to a functional improvement of the protein properties. These results support the application of the CRISPR editing approach to knock out COL6A1 mutated alleles and rescue the UCMD phenotype in patient-derived fibroblasts.
2024-09-18 | Cell-derived matrices mechanics as a functional read-out in Collagen VI-related Congenital Muscular Dystrophies
Collagen VI-related congenital muscular dystrophies (COL6-RDs) are a set of neuromuscular conditions caused by pathogenic variants found in any of the three COL6 genes. The phenotypic expression of the disease does not directly correlate with the genetic background producing an overlapping spectrum of clinical phenotypes that goes from the mild Bethlem myopathy (BM) to the severe Ulrich congenital muscular dystrophy (UCMD). Diagnosis includes genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability. The development of new tools able to identify phenotype traits can significantly contribute to the diagnosis and prognosis of COL6-RDs. Mutations occurring in COL6 genes result in deficiency or dysfunction of COL6 incorporated into the extracellular matrix (ECM) of connective tissues, affecting its fibrillar structure. Our research group has established personalized pre-clinical models of COL6-RDs based on cell-derived matrices (CDMs), which allowed the direct observation of the fibrillar organization of the ECM in samples derived from patients, and to compare features amongst different phenotypes. Here, we have characterized the mechanical properties of CDMs from patients using atomic force microscopy-based force spectroscopy (AFM-FS). We observed that the elastic modulus (E) varies with the phenotype, and that it correlates with COL6 organization in the CDMs. We additionally used AFM-FS to evaluate matrices derived from genetically edited cells, which resulted in E value restoration compared to control samples. Altogether, these results anticipate the potential of mechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
2024-03-22 | Allele-specific CRISPR/Cas9 editing inactivates a single nucleotide variant associated with collagen VI muscular dystrophy
The application of allele-specific gene editing tools can expand the therapeutic options for dominant genetic conditions, either via gene correction or via allelic gene inactivation in situations where haploinsufficiency is tolerated. Here, we used allele-targeted CRISPR/Cas9 guide RNAs (gRNAs) to introduce inactivating frameshifting indels at a single nucleotide variant in the COL6A1 gene (c.868G>A; G290R), a variant that acts as dominant negative and that is associated with a severe form of congenital muscular dystrophy. We expressed spCas9 along with allele-targeted gRNAs, without providing a repair template, in primary fibroblasts derived from four patients and one control subject. Amplicon deep-sequencing for two gRNAs tested showed that single nucleotide deletions accounted for the majority of indels introduced. While activity of the two gRNAs was greater at the G290R allele, both gRNAs were also active at the wild-type allele. To enhance allele-selectivity, we introduced deliberate additional mismatches to one gRNA. One of these optimized gRNAs showed minimal activity at the WT allele, while generating productive edits and improving collagen VI matrix in cultured patient fibroblasts. This study strengthens the potential of gene editing to treat dominant-negative disorders, but also underscores the challenges in achieving allele selectivity with gRNAs.
2023-08-05 | New Clinical and Immunofluorescence Data of Collagen VI-Related Myopathy: A Single Center Cohort of 69 Patients
Pathogenetic mechanism recognition and proof-of-concept clinical trials were performed in our patients affected by collagen VI-related myopathies. This study, which included 69 patients, aimed to identify innovative clinical data to better design future trials. Among the patients, 33 had Bethlem myopathy (BM), 24 had Ullrich congenital muscular dystrophy (UCMD), 7 had an intermediate phenotype (INTM), and five had myosclerosis myopathy (MM). We obtained data on muscle strength, the degree of contracture, immunofluorescence, and genetics. In our BM group, only one third had a knee extension strength greater than 50% of the predicted value, while only one in ten showed similar retention of elbow flexion. These findings should be considered when recruiting BM patients for future trials. All the MM patients had axial and limb contractures that limited both the flexion and extension ranges of motion, and a limitation in mouth opening. The immunofluorescence analysis of collagen VI in 55 biopsies from 37 patients confirmed the correlation between collagen VI defects and the severity of the clinical phenotype. However, biopsies from the same patient or from patients with the same mutation taken at different times showed a progressive increase in protein expression with age. The new finding of the time-dependent modulation of collagen VI expression should be considered in genetic correction trials.
other
2026-04-22 | Collagen VI–Related Myopathies: An Educational Overview of Molecular Pathogenesis, Variability of Clinical Presentations Spectrum, Diagnostic Approaches and Management Strategies
Collagen VI–related myopathies (COL6-RM) encompass a broad clinical spectrum of inherited neuromuscular disorders ranging from severe Ullrich congenital muscular dystrophy to milder Bethlem myopathy, caused by pathogenic variants in COL6A1, COL6A2, and COL6A3. The pathogenic disruptions in collagen VI compromise extracellular matrix stability, impair autophagic flux, promote mitochondrial permeability transition, and alter fibroblast–myofiber signaling. These disorders are characterized by proximal muscle weakness, joint contractures, distal hyperlaxity, and respiratory compromise. Advances in basic science have revealed that collagen VI deficiency disrupts extracellular matrix (ECM) integrity, impairs autophagy, induces mitochondrial dysfunction, and alters the myomatrix microenvironment, collectively driving progressive muscle degeneration. Diagnosis relies on a multimodal approach that integrates clinical assessment with muscle MRI, histopathology, and next-generation sequencing. Management remains largely supportive; however, emerging strategies, including autophagy enhancers, mitochondrial permeability transition pore (mPTP) inhibitors, extracellular matrix–targeting agents, and genebased therapies show promise for disease modification. Advances in molecular biology have reshaped the understanding of COL6-RM and opened new avenues for targeted treatment. Robust natural history studies and biomarker development are needed to accelerate translational progress. The objective is to synthesize current evidence regarding pathogenesis, clinical presentation, diagnostic modalities, and evolving therapeutic approaches in COL6-RM. This review integrates and synthesizes findings from molecular pathogenesis, diagnostic tools, clinical spectrum, imaging studies, and evolving management while highlighting future therapeutic directions with emphasis on recent mechanisms involving extracellular matrix dysfunction, autophagy impairment, mitochondrial dysregulation, and myomatrix remodeling.
2025-12-30 | Tendon Dysfunction in Collagen VI-Related Myopathies: Novel Mechanistic Insights with Therapeutic Potential.
Collagen VI-related myopathies (COL6-RM) encompass a spectrum of disorders characterized by muscle weakness, joint contractures, and connective tissue abnormalities resulting from mutations in the collagen VI genes. While muscle pathology has been extensively studied, tendon dysfunction has emerged as a critical yet underexplored contributor to disease severity, particularly in the development of joint contractures. Tendons from patients and animal models show disrupted collagen fibrillogenesis, altered extracellular matrix (ECM) composition, and impaired cellular mechanotransduction. Various defects in ECM remodeling pathways further exacerbate tendon pathology. Importantly, current clinical management remains limited to orthopedic interventions with modest outcomes, and targeted pharmacological strategies or gene-editing therapies are not yet available for clinical application. Therefore, understanding the basic pathogenic mechanisms underlying tendon dysfunction is essential for identifying novel therapeutic targets. This review provides a comprehensive synthesis of current understanding and recent advances concerning the role of mutated collagen VI in cellular and molecular mechanisms underlying tendon dysfunction. Emphasis is placed on the role of mutated collagen VI in the modulation of key signaling pathways related to mechanotransduction and primary cilium function in COL6-RM. By discussing these multifaceted contributions to disease pathogenesis, this review outlines future research directions in the field and highlights potential pathways for targeted therapeutic interventions.
2024-06-25 | Phase 1 Open-Label Study of Omigapil in Patients With LAMA2- or COL6-Related Dystrophy.
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dyw/dyw) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy2J/dy2J) LAMA2-RD mouse model and the (Col6a1-/-) COL6-RD mouse model demonstrated decreased apoptosis. A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data. Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC0-24h) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study. This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations. This study provides Class IV evidence of omigapil in a dose-finding phase 1 study. Clinical Trials NCT01805024.
2022-01-06 | Ablation of collagen VI leads to the release of platelets with altered function.
Hemostatic abnormalities and impaired platelet function have been described in patients affected by connective tissue disorders. We observed a moderate bleeding tendency in patients affected by collagen VI-related disorders and investigated the defects in platelet functionality, whose mechanisms are unknown. We demonstrated that megakaryocytes express collagen VI that is involved in the regulation of functional platelet production. By exploiting a collagen VI-null mouse model (Col6a1-/-), we found that collagen VI-null platelets display significantly increased susceptibility to activation and intracellular calcium signaling. Col6a1-/- megakaryocytes and platelets showed increased expression of stromal interaction molecule 1 (STIM1) and ORAI1, the components of store-operated calcium entry (SOCE), and activation of the mammalian target of rapamycin (mTOR) signaling pathway. In vivo mTOR inhibition by rapamycin reduced STIM1 and ORAI1 expression and calcium flows, resulting in a normalization of platelet susceptibility to activation. These defects were cell autonomous, because transplantation of lineage-negative bone marrow cells from Col6a1-/- mice into lethally irradiated wild-type animals showed the same alteration in SOCE and platelet activation seen in Col6a1-/- mice. Peripheral blood platelets of patients affected by collagen VI-related diseases, Bethlem myopathy and Ullrich congenital muscular dystrophy, displayed increased expression of STIM1 and ORAI1 and were more prone to activation. Altogether, these data demonstrate the importance of collagen VI in the production of functional platelets by megakaryocytes in mouse models and in collagen VI-related diseases.
2017-12-15 | Transcriptome profiling identifies regulators of pathogenesis in collagen VI related muscular dystrophy
Objectives The collagen VI related muscular dystrophies (COL6-RD), Ullrich congenital muscular dystrophy (UCMD) and Bethlem myopathy (BM) are among the most common congenital muscular dystrophies and are characterized by distal joint laxity and a combination of distal and proximal joint contractures. Inheritance can be dominant negative (DN) or recessive depending on the type and location of the mutation. DN mutations allow incorporation of abnormal chains into secreted tetramers and are the most commonly identified mutation type in COL6-RD. Null alleles (nonsense, frameshift, and large deletions) do not allow incorporation of abnormal chains and act recessively. To better define the pathways disrupted by mutations in collagen VI, we have used a transcriptional profiling approach with RNA-Seq to identify differentially expressed genes in COL6-RD individuals from controls. Methods RNA-Seq allows precise detection of all expressed transcripts in a sample and provides a tool for quantification of expression data on a genomic scale. We have used RNA-Seq to identify differentially expressed genes in cultured dermal fibroblasts from 13 COL6-RD individuals (8 dominant negative and 5 null) and 6 controls. To better assess the transcriptional changes induced by abnormal collagen VI in the extracellular matrix (ECM); we compared transcriptional profiles from subjects with DN mutations and subjects with null mutations to transcriptional profiles from controls. Results Differentially expressed transcripts between COL6-RD and control fibroblasts include upregulation of ECM components and downregulation of factors controlling matrix remodeling and repair. DN and null samples are differentiated by downregulation of genes involved with DNA replication and repair in null samples. Conclusions Differentially expressed genes identified here may help identify new targets for development of therapies and biomarkers to assess the efficacy of treatments.
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Drug Discovery Landscape
1 orphan drug designation for Collagen VI-related congenital muscular dystrophy.
1 orphan drug designation for Collagen VI-related congenital muscular dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Omigapil maleate | small molecules | EMA | Santhera Pharmaceuticals (Deutschland) GmbH |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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