RARE DISEASE
Oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy
Oculopharyngeal muscular dystrophy
Synonyms: OPMD
Synonyms: OPMD
Synonyms: OPMD
Drug discovery
3
drugs
With orphan designations
Overview
Oculopharyngeal muscular dystrophy (OPMD) is a rare autosomal dominant disorder caused by PABPN1 gene mutations, characterized by late-onset ptosis, dysphagia, and proximal limb weakness. Symptoms typically emerge in the 40s–50s, progressing slowly. Diagnosis involves genetic testing and clinical evaluation. Management focuses on symptom relief through surgical interventions (e.g., blepharoplasty, cricopharyngeal myotomy) and supportive therapies [1][7][18]. Life expectancy is near-normal with proper care, though complications like aspiration pneumonia pose risks [7][19].
Burden
Physical: Progressive dysphagia increases aspiration and malnutrition risks; mobility loss necessitates assistive devices [4][6][9].
Psychosocial: Chronic fatigue, pain, and social isolation due to visible ptosis and swallowing difficulties [4][13].
Economic: Requires lifelong multidisciplinary care (neurology, ENT, nutrition) [9][19].
Therapies
Surgical: Ptosis correction (frontalis sling), dysphagia management (cricopharyngeal myotomy, Botox injections) [6][8][18].
Supportive: Speech therapy, gastrostomy for severe dysphagia; physiotherapy for limb weakness [6][8][9].
Investigational: RNA replacement, AAV-mediated gene therapy, and trehalose (Phase IIb trial) [3][12][17].
Categories: rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders
Research Papers
165 drug discovery papers about Oculopharyngeal muscular dystrophy, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
165 drug discovery papers about Oculopharyngeal muscular dystrophy, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-06-16 | Distinct roles of IDR and CCD domains control PABPN1 aggregation and enable therapeutic rescue
Abstract PABPN1 is a multifunctional protein whose expression is tightly regulated to maintain cellular homeostasis. PABPN1 dysregulation contributes to both common acquired diseases, such as bladder cancer, and rare inherited disorders, including oculopharyngeal muscular dystrophy (OPMD). In OPMD, PABPN1 forms insoluble aggregates that reduce its functional levels, leading to genome-wide shifts in alternative polyadenylation (APA) at 3′-UTRs and disruption of mRNA metabolism, including nuclear export and translation. OPMD is caused by a short alanine expansion at the N-terminus of PABPN1 within an intrinsically disordered region (IDR) followed by a coiled-coil domain (CCD). How these domains contribute to PABPN1 function and aggregation remains unclear. Here, we show that the N-terminal IDR promotes aggregation and modulates protein-protein interactions with longer IDRs suppressing interaction between PABPN1 and its binding partners. We further demonstrate that the CCD has dual functions: its N-terminal domain dictates PABPN1 stability, whereas its C-terminal domain enhances the PABPN1 interactome. We identified a naturally occurring variant lacking exon 1 encoding the IDR and the CCD N-terminal domain (named trPAB). That variant forms a stable, non-aggregating protein isoform. Interactome analysis and structural modeling indicate improved molecular function by restoring PABPN1 activity, APA profiles, and cellular phenotypes in OPMD and bladder cancer models. Importantly, delivery of trPAB via Adeno-associated viral vector in an OPMD mouse model improves muscle histopathology, supporting its potential as a therapeutic strategy. A mechanistic basis of a novel gene therapy approach for OPMD Top panel: A schematic presentation of three PABPN1 variant functional states. Left: the normal full-length protein interacts with key RNA binding protein (RBP) partners supporting normal cellular function. Middle: A pathogenic full-length alanine-expanded PABPN1 leads to protein aggregation, resulting in limited interactors, dysfunctional complexes and impaired cellular processes. Right: a truncated natural variant (trPAB), not associated with OPMD pathology, shows enhanced stability and reduced aggregation, suggesting a potential protective or “super functional” profile. The bottom panel translates these mechanistic insights into therapeutic strategy. In cell models, expression of trPAB is associated with reduced protein aggregation, restoration of normal cellular function, and improved myogenesis. These effects are recapitulated in a relevant animal model of OPMD, where trPAB treatment leads to decreased aggregation, functional recovery, and reversal of muscle atrophy. Our study supports the rationale for leveraging a stabilized PABPN1 variant as a novel gene therapy approach to counteract aggregation-driven pathology in OPMD. Highlights The central coiled-coil domain (CCD) of PABPN1 has two opposing functions: its N-terminal region stabilizes the protein, while its C-terminal region promotes stability but hampers aggregation. At the N-terminus, an intrinsically disordered region (IDR) acts as a gatekeeper for protein interactions. The alanine tract, including its pathogenic expansion, restricts this interactome, limiting PABPN1 binding capacity. We identified a naturally occurring PABPN1 isoform, trPAB, which lacks exon 1, including the IDR and the N-terminal portion of the CCD. trPAB forms a stable and functional protein and exerts beneficial effects in muscle cells. Functionally, trPAB rescues key cellular phenotypes in bladder cancer cells and reverses nuclear aggregation and muscle atrophy in a mouse model of OPMD.
2025-05-23 | Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics
Abstract Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease caused by modest alanine expansion at the amino terminus of the nuclear polyadenosine RNA binding protein PABPN1. PABPN1 is expressed ubiquitously and is involved in multiple steps in RNA processing including optimal cleavage and polyadenylation, polyadenylation signal selection, and export of polyadenylated RNAs from the nucleus. Expanded PABPN1 forms aggregates in a subset of muscle nuclei, but PABPN1 levels are paradoxically low in muscle compared to other tissues. Despite several studies in model systems and patient tissues, it remains unclear whether alanine expansion directly impairs PABPN1 function. The molecular mechanisms leading to OPMD pathology are poorly understood. Here we used a proximity labeling approach to better understand the effect of alanine expansion on PABPN1 function in a cell culture model of skeletal muscle. To avoid the confounding factor of overexpression, PABPN1 constructs containing a carboxy-terminal TurboID tag were expressed in skeletal myotubes at near native levels using an inducible promoter. Although non-expanded PABPN1-TurboID was able to complement RNA export and myoblast differentiation defects caused by deficiency of endogenous PABPN1, alanine expanded PABPN1-TurboID was not. Comparative proteomics revealed increased interaction between expanded PABPN1 and RNA splicing and polyadenylation machinery and follow-up studies identified a dominant negative effect on RNA export in differentiated myotubes. These data indicate that alanine expansion can impair PABPN1 function regardless of the presence of wild type PABPN1 and support a model wherein both loss function and dominant negative effects of expanded PABPN1 contribute to OPMD pathology. Author summary Oculopharyngeal muscular dystrophy (OPMD) is a late onset muscle disease that, unlike other muscular dystrophies, causes progressive weakness primarily in muscles of the face and head. OPMD is most commonly inherited in a dominant fashion and is caused by small expansions in the gene encoding the RNA binding protein PABPN1. Despite the fact that PABPN1 is expressed ubiquitously and contributes to multiple steps in RNA processing, its expansion causes disease almost exclusively in skeletal muscle. The precise molecular events leading to OPMD disease onset have been difficult to characterize as it is challenging to separate functions expanded versus non-expanded PABPN1 in muscle without the confounding factor of overexpressing tagged fusion proteins. Here we fused expanded and non-expanded PABPN1 to the modified biotin ligase TurboID to label proximal proteins. PABPN1-TurboID fusions were expressed in a cell culture model of skeletal muscle at near-native levels. Using these constructs, we discovered that expanded PABPN1 is less functional than non-expanded PABPN1 and causes dominant negative effects on some PABPN1 functions. These findings support a model where both loss of function and dominant negative effects contribute to the molecular pathology of OPMD.
2022-07-20 | Botulinum toxin treatment improves dysphagia in patients with oculopharyngeal muscular dystrophy and sporadic inclusion body myositis.
Dysphagia can be troublesome in sporadic inclusion body myositis (sIBM) and oculopharyngeal muscular dystrophy (OPMD), but no established treatment exists. Cricopharyngeal muscle botulinum toxin injection has at case level been reported to be effective. We evaluated safety and efficacy of botulinum toxin injections in the cricopharyngeal muscle in patients with dysphagia due to sIBM or OPMD. Participants were included from our outpatient clinic. Cricopharyngeal constriction was confirmed by laryngoscopy. After EMG confirmation of needle placement in the cricopharyngeal muscle, botulinum toxin A was injected in awake patients. An individualized dose of 5-10 units of botulinum toxin A was applied initially and titrated up a maximum of 3 times. Outcome measures were change in dysphagia questionnaire, timed cold-water swallow test and subjective dysphagia status (worse, unchanged, improved). Due to the need for individualized dosing and a limited number of available patients, an uncontrolled, un-blinded design was used. Thirteen patients, 3 with OPMD, received at least 1 injection. In the dysphagia questionnaire, all but 2 subjects, none with subjective worsening, improved (p < 0.001). Subjectively, seven felt an improvement, 4 no change and 2 a worsening. No overall change was seen the timed cold-water swallow test. No serious adverse events were observed. Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods. EudraCT-number: 2014-002210-23.
2017-09-12 | Effects of botulinum toxin injections in the cricopharyngeal muscle of OPMD and IBM myopathies with dysphagia
Certain myopathies have dysphagia as a pronounced and very troublesome symptom, but no established treatment exists. Botulinum toxin injection in the cricopharyngeal muscle has at case level been reported to be effective. To systematically evaluate the safety and efficacy of injections of botulinum toxin in the cricopharyngeal muscle in patients with dysphagia due to inclusion body myositis (IBM) or oculopharyngeal muscular dystrophy (OPMD). Patients with confirmed diagnoses of IBM or OPMD and dysphagia were included if no other cause for dysphagia was present, and if dysphagia, assessed by a timed water swallow test, a dysphagia questionnaire and by meal registration, was pronounced. Additional baseline registration included body weight, number of pneumonia episodes, muscle strength and enzyme measurements. Initially, laryngoscopia was performed followed by needle electromyography to confirm activity in the cricopharyngeal muscle and to establish needle placement. Botulinum toxin was then injected through the hollow EMG needle. An individualized dose of 5–10 units was applied bilaterally the first time and the dose was then titrated up with at least 12 weeks' intervals. Suspected side effects were noted at each visit. Outcome measures were change in timed water swallowing test, dysphagia questionnaire and meal registration. 12 subjects were included, 3 with OPMD. Preliminary results from 6 subjects show that 4 felt a clear improvement, whereas 2 were excluded due to that a worsening was suspected based on subjective observations and worsening in the meal registration assessment. In the dysphagia questionnaire, however, every single subject improved (p < 0.001). No overall change was seen in the meal registration assessment and the timed water swallow test. Preliminary results suggest a positive effect on dysphagia of cricopharyngeal botulinum toxin in patients with OPMD and IBM.
2014-11-03 | Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region‐dependent manner
Key points Millions of elderly individuals have dysphagia, a debilitating and life‐threatening condition in which the ability to swallow is impaired. Several muscles surround the three regions of the pharynx, which are essential for proper swallowing, yet the effects of ageing and disease on these muscles are not well understood. We demonstrate that the fibre size of murine pharyngeal muscles is differentially affected by ageing and muscular dystrophy depending on their location within the pharynx. Using a mouse model of an age‐associated dysphagic disease (oculopharyngeal muscular dystrophy), we show that overexpression of wild‐type polyadenylate binding nuclear protein 1 in muscle tissue prevents age‐related dysphagia and age‐related muscle atrophy of laryngopharyngeal muscles. These results demonstrate that mice are an excellent model for studying mechanisms of ageing and disease on pharyngeal muscle physiology, and such studies could lead to new therapies for individuals with dysphagia. Abstract The inability to swallow, or dysphagia, is a debilitating and life‐threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild‐type mice depending on the particular muscle analysed. Furthermore, wild‐type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild‐type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild‐type A10 PABPN1 was protective against age‐related muscle atrophy in the laryngopharynx and prevented the development of age‐related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region‐dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia.
small molecules
2026-08-06 | Direct Observationof Structural Unraveling in PABPN1Polyalanine Expansions
Abstract Above-threshold homorepeat expansions promote alternative conformations and irreversible aggregation, driving the malfunction of numerous disease-associated proteins. A detailed understanding of the structural remodeling events in pathogenic mutants enables the identification of key elements determining aberrant structure formation. Here, we describe in high resolution the structural transitions in Poly(A) Binding Protein Nuclear 1 (PABPN1), in which polyalanine expansions beyond a +1 single additional residue cause Oculopharyngeal Muscular Dystrophy (OPMD). PABPN1’s polyalanine tract in its wild-type (containing 10 consecutive alanine residues) and +1 and +8 variants populate alternative polymorphs, with α-helical conformations being increasingly favored and rigid upon expansion. Spontaneous slow unfolding was observed across variants in real time by Nuclear Magnetic Resonance (NMR) spectroscopy, indicating that increased dynamics at the C-terminal end of the polyalanine helix emerges as an early unfolding event associated with functional impairment. Our data help to define key mechanistic features in pathogenic misfunction induced by homorepeat expansions and identify specific structural motifs as potential targets for fragment-based binders to restore protein functionality in polyalanine expansion disorders.
2026-07-28 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery-Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
2026-04-30 | Molecular and therapeutic effects of bioactive compounds-incorporated mucoadhesive buccal patch targeting oral potentially malignant disorders.
Oral potentially malignant disorders (OPMD) are associated with high risk of progression to oral squamous cell carcinoma (OSCC) and remain difficult to manage, due to limited effective localized therapies, underscoring the urgent need for novel, targeted drug delivery systems. A mucoadhesive buccal patch loaded bioactive components such as isotretinoin, bromelain, and limonene (IBL patch) was fabricated and evaluated for its anticancer potential against OPMD-associated OSCC. The cytotoxic study demonstrated that the IBL patch significantly reduced CAL-27 cells viability and found IC50 value around 650 μg/mL, while exhibiting minimal cytotoxicity toward human gingival fibroblast (HGF) cells, indicating selective anticancer activity. In comparison to HGF cells, the IBL patch significantly reduced the migration and invasion of CAL-27 cells. Colony formation assays further confirmed that the IBL patch significantly suppressed the long-term proliferative and clonogenic potential of CAL-27 cells, without affecting HGF cells division. Genotoxicity analysis revealed increased micronucleus formation in CAL-27 cells, suggesting DNA damage-mediated apoptotic induction. Then IBL patch showed molecular effects by suppressing EMT and fibrosis associated TGF-β/SMAD signaling, inhibiting inflammatory (NF-κB), Wnt/β-Catenin pathways and Cytokeratin 17 (CK-17) and restoring epithelial identity through E-Cadherin and CK-18 upregulation. Furthermore, pathway analysis in both monolayer and co-culture inflammatory models demonstrated that the IBL patch effectively suppressed LPS-induced inflammatory markers, including TGF-β, MMP-2, IL-6, and TNF-α expression. Oral acute toxicity testing (OECD 423) confirmed safety of the IBL patch, with no mortality or adverse effects up to 2000 mg/kg (LD₅₀ > 2000 mg/kg; GHS Category 5). Collectively, these findings highlights that the IBL mucoadhesive buccal patch has therapeutic potential against OPMD and controlling pathological epithelial remodeling.
2026-04-02 | Cysteine proteases in oral potentially malignant disorders: Molecular drivers, diagnostic signatures, and therapeutic opportunities.
Cysteine proteases are crucial enzymes regulating protein turnover, apoptosis, signalling, and tissue remodelling, and have emerged as important regulators of the oral epithelial microenvironment with increasing evidence implicating them in the progression of oral potentially malignant disorders (OPMDs) and their potential contribution to malignant transformation toward oral squamous cell carcinoma (OSCC). Dysregulated expression of these enzymes influences key molecular pathways, notably NF-κB, MAPK, protease-activated receptor (PAR) signalling, and apoptotic cascades, although the extent to which individual cysteine proteases act as primary drivers, facilitators of tumour-associated microenvironmental remodelling, or biomarkers of disease progression remains incompletely defined, which govern extracellular matrix remodelling, inflammation, proliferation, migration, and immune evasion, processes associated with malignant progression. Their diagnostic potential is evident through distinct expression patterns in saliva and tissue, suggesting potential utility as adjunct salivary biomarkers for early detection; however, their diagnostic performance relative to established approaches such as toluidine blue staining, autofluorescence imaging, and cytopathological assessment remains to be systematically evaluated. On the therapeutic front, approaches such as selective inhibitors, plant-derived proteases, prodrugs, and multifunctional theranostic agents have been explored experimentally for modulating inflammation, fibrosis, and tumour invasion, while innovative drug delivery strategies aim to increase specificity and reduce systemic toxicity. Nevertheless, most cysteine-protease-targeted interventions remain at preclinical or early translational stages, and clinical validation in oral diseases is currently limited. However, challenges including resistance mechanisms, lack of absolute selectivity, and potential off-target effects necessitate refined computational and experimental strategies for rational inhibitor design. Furthermore, the relative contribution of individual cysteine proteases across different OPMD subtypes remains insufficiently characterized. Future advances lie in validating protease-based biomarkers across diverse populations and embedding them into personalized medicine frameworks.
2026-02-18 | GGC repeat expansions within new open reading frames are translated into toxic polyglycine proteins in oculopharyngodistal myopathy.
A total of 3-6% human genome is composed of microsatellite sequences, which are short DNA elements composed of two to six nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as noncoding, which raises questions about their pathogenicity. Here we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without oculopharyngeal myopathy leukoencephalopathy are located within previously unrecognized open reading frames (ORFs), resulting in their translation into new polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting the expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet-unrecognized small ORFs.
antibodies
2023-09-29 | Generation and Immuno-inflammatory Checkpoints in Oral Cavity Cancers
Oral malignancies are responsible for a considerable portion of cancer-related deaths worldwide. Even though survival rates have increased recently, new treatments are being explored to slow the advancement of the disease and enhance outcomes, especially in cases of oral cavity squamous cell carcinoma (OSCC) and oral potentially malignant diseases (OPMDs). Immunotherapy is a novel therapeutic approach that targets immune checkpoint molecules such as programmed cell death protein-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4, lymphocyte-activated gene 3, and T cell immunoglobulin mucin 3 in order to enhance the host’s immune response against malignancies and impede the growth and metastasis of cancer cells. Accordingly, a systematic review was performed by scanning five databases for keywords related to immune checkpoint inhibitors, along with oral malignancies, oral pathologies, and OPMDs, in order to describe the current state of their use and efficacy in these disorders. For this purpose, 644 unique publications published between 2004 and 2019 were found, 76 of which were judged to be appropriate for the study and produced 8826 samples. PD-1 and PD-L1 are expressed in most OPMD and OSCC samples, and their expression is associated with worse survival rates and greater rates of progression. Two immunotherapy drugs targeting PD-1, namely, pembrolizumab and nivolumab, have been demonstrated to enhance disease outcomes and increase survival rates, especially when combined with radiation or chemotherapy. Despite the equivocal nature of the available data, there is support for the prognostic and predictive usefulness of immune checkpoint molecules, notably PD-L1, and multiple studies support the useful use of immune checkpoint inhibitors in the management of OSCC.
2022-11-22 | Systemic Delivery of a Monoclonal Antibody to Immunologically Block Myostatin in the A17 Mouse Model of OPMD.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset rare muscle disease affecting approximately 1 in 80,000 individuals worldwide. However, it can affect as much as 1:600 individuals in some populations due to a strong founder effect. The muscle pathology is characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and limb weakness at later stages of disease progression. The genetic defect is associated with significant fibrotic deposition and atrophy in affected muscles. No treatments are available to cure the disease. Only surgical techniques to correct ptosis and swallowing are currently possible, though they carry a risk of recurrence. Myostatin is a negative regulator of muscle growth, and several strategies to downregulate its expression have been developed with the aim of improving muscle mass and strength in muscular pathologies. We recently showed that weekly systemic treatment of the A17 murine model of OPMD with a monoclonal antibody for myostatin improves body and muscle mass, increases muscle strength, and reduces muscle fibrosis. Here, we describe the methodology for repeated intraperitoneal delivery of myostatin antibody in the murine model. Furthermore, we detail the most relevant analyses to assess histopathological and functional improvements of this treatment in this mouse model.
2020-03-05 | Inhibition of Myostatin Reduces Collagen Deposition in a Mouse Model of Oculopharyngeal Muscular Dystrophy (OPMD) With Established Disease
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disease presented by ptosis, dysphagia, and limb weakness. Affected muscles display increased fibrosis and atrophy, with characteristic inclusion bodies in the nucleus. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to improve symptoms in models of muscular dystrophy.We systemically administered a monoclonal antibody to block myostatin in the A17 mouse model of OPMD at 42 weeks of age. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which serum and histological analyses were performed on muscle samples.The administration of the antibody resulted in a significant decrease in serum myostatin and collagen deposition in muscles. However, minimal effects on body mass, muscle mass and myofiber diameter, or the density of intranuclear inclusions (INIs) (a hallmark of disease progression of OPMD) were observed.This study demonstrates that inhibition of myostatin does not revert muscle atrophy in a mouse model with established OPMD disease, but is effective at reducing observed histological markers of fibrosis in the treated muscles.
2019-05-07 | Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)
Abstract Background Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset muscle disease affecting one per 80 000 of the general population characterized by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterized by increased fibrosis and atrophy. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to ameliorate symptoms in dystrophic muscles. Methods In this study, we performed a systemic delivery of a monoclonal antibody to immunologically block myostatin in the A17 mouse model of OPMD. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples. Results This treatment significantly ( P < 0.01) improved body mass (11%) and muscle mass (for the tibialis anterior and extensor digitorum longus by 19% and 41%) in the A17 mice treated with RK35 when compared to saline controls. Similarly, a significantly ( P < 0.01) increased muscle strength (18% increase in maximal tetanic force) and myofibre diameter (17% and 44% for the tibialis anterior and extensor digitorum longus), and reduced expression of markers of muscle fibrosis (40% reduction in area of expression), was also observed. No change in the density of intranuclear inclusions (a hallmark of disease progression of OPMD) was however observed. Conclusions Our study supports the clinical translation of such antibody‐mediated inhibition of myostatin as a treatment of OPMD. This strategy has implications to be used as adjuvant therapies with gene therapy based approaches, or to stabilize the muscle prior to myoblast transplantation.
2010-03-10 | Structural basis for a PABPN1 aggregation‐preventing antibody fragment in OPMD
Oculopharyngeal muscular dystrophy is caused by small alanine expansions in polyadenylate binding protein nuclear 1 (PABPN1) protein resulting in its intranuclear accumulation in skeletal muscle. 3F5 llama antibody specifically interferes with the PABPN1 aggregation process in vitro and in vivo. To understand the structural basis for its epitope recognition we mapped the binding interface of 3F5 with PABPN1 and provide a structural model of the 3F5-PABPN1 complex. We show that 3F5 complementarity determining regions create a cavity in which PABPN1 alpha-helix domain resides by involving critical residues previously implicated in the aggregation process. These results may increase our understanding of the PABPN1 aggregation mechanism and the therapeutic potential of 3F5.
oligonucleotides
2026-01-01 | THE MICROECOLOGICAL AETIOLOGY OF ORAL CANCER: DECIPHERING THE ROLE OF THE ORAL MICROBIOME IN THE MALIGNANT TRANSFORMATION OF OPMDS
The malignant transformation of oral potentially malignant disorders (OPMDs) into oral squamous cell carcinoma (OSCC) has traditionally been viewed through the narrow lens of host genomic instability and cumulative environmental mutagenesis. However, the diagnostic paradigm is currently undergoing a profound shift. Advanced multi-omics sequencing has unveiled a vast, highly active oral microecosystem that does not merely colonise neoplastic tissue opportunistically, but actively orchestrates the aetiopathogenesis of the tumour. This review exhaustively examines the transition from microbial haemostasis to pathogenic dysbiosis within OPMDs. By mapping the specific mechanisms through which keystone periopathogens—namely Fusobacterium nucleatumand Porphyromonas gingivalis—induce the epithelial-mesenchymal transition (EMT), hyperactivate inflammatory signalling cascades, and subvert local immune surveillance, this manuscript provides a comprehensive molecular framework. Integrating microbial landscaping into routine oral pathology offers profound new avenues for predicting malignant transformation and designing targeted microecological therapies.
2025-09-01 | 564PDevelopment of an antisense oligonucleotide therapy for oculopharyngeal muscular dystrophy using iPSC-derived myocytes
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder prevalent in French Canadians (1:1000). It causes progressive ptosis, dysphagia, and proximal weakness, with no disease-modifying therapy available. OPMD results from GCG expansions in the PABPN1 gene, with patients commonly having 13-15 repeats versus 10 in healthy individuals. We aim to develop a cellular OPMD model and evaluate antisense oligonucleotides (ASOs) as a therapy by 1) Generating CRISPR-edited induced pluripotent stem cells (iPSCs) with 13 GCN repeats in PABPN1, and 2) Differentiating these cells into myocytes for investigating candidate ASOs. The expanded GCG repeats will be introduced into KOLF2.1J iPSCs by using a pair of single guide RNAs combined with a Cas9 nickase. After validation, cells will be differentiated into myocytes using PiggyBac-Tet-On-MyoD1. Myocytes will be characterized by immunofluorescence for myogenic markers and PABPN1 pathology. We will test phosphorothioate-modified ASOs with LNA or 2′-MOE chemistry targeting expanded repeats to reduce mutant PABPN1 while preserving wild-type levels. Preliminary experiments showed that the designed guide RNAs created a staggered double-strand break in the PABPN1 gene, which is ideal to favor homology-directed repair while minimizing off-target effects. In addition, wild type iPSCs were successfully differentiated into homogeneous myotubes culture expressing myosin filaments. We anticipate creating a model displaying PABPN1 nuclear aggregates and identifying ASOs that selectively target the expanded allele while preserving wild-type PABPN1 function, essential for normal muscle physiology. This project establishes a foundation for developing a disease-modifying therapy for OPMD through a human cellular model and allele-specific ASOs, potentially leading to clinical translation for this untreatable condition.
2023-08-09 | Oculopharyngeal muscular dystrophy mutations link the RNA-binding protein HNRNPQ to autophagosome biogenesis.
Autophagy is an intracellular degradative process with an important role in cellular homeostasis. Here, we show that the RNA binding protein (RBP), heterogeneous nuclear ribonucleoprotein Q (HNRNPQ)/SYNCRIP is required to stimulate early events in autophagosome biogenesis, in particular the induction of VPS34 kinase by ULK1-mediated beclin 1 phosphorylation. The RBPs HNRNPQ and poly(A) binding protein nuclear 1 (PABPN1) form a regulatory network that controls the turnover of distinct autophagy-related (ATG) proteins. We also show that oculopharyngeal muscular dystrophy (OPMD) mutations engender a switch from autophagosome stimulation to autophagosome inhibition by impairing PABPN1 and HNRNPQ control of the level of ULK1. The overexpression of HNRNPQ in OPMD patient-derived cells rescues the defective autophagy in these cells. Our data reveal a regulatory mechanism of autophagy induction that is compromised by PABPN1 disease mutations, and may thus further contribute to their deleterious effects.
2023-08-03 | Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.
Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.
2022-05-02 | Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
other
2024-10-18 | Sequential development of parkinsonism in two patients with oculopharyngodistal type myopathy in GIPC1-related repeat expansion disorder.
A heterozygous CGG repeat expansion in 5' untranslated region (5' UTR) of GIPC1 is one of the causative factors of oculopharyngodistal myopathy (OPDM), an adult-onset hereditary muscle disease characterized by progressive ptosis, ophthalmoplegia, and facial, bulbar, and distal limb muscle weakness. CGG repeat expansion in GIPC1 has also been reported to be associated with Parkinson's disease, but these patients did not exhibit myopathic symptoms. We experienced two unrelated cases of oculopharyngeal type myopathy with CGG repeat expansion in GIPC1 presenting parkinsonism after exhibiting myopathic symptoms. Both cases showed p62-positive intranuclear inclusions in the skin, similar to those in NOTCH2NLC-related disorders. Our cases suggest that GIPC1-related repeat expansions may be associated with a broad spectrum and tissue-differential neuromuscular manifestations, indicating a common mechanism between OPDM2 and other CGG-repeat expansion diseases. It is important to note OPDM2 patients' central neurological symptoms, as myopathic symptoms may obscure central nervous system manifestations.
2024-04-01 | Our journey with François Gros.
Gillian Butler-Browne began working on muscle at the Institut Pasteur in the laboratory of François Gros in 1978. She characterized the expression profile of different myosin isoforms during both human and rodent development. Vincent Mouly joined this laboratory for his PhD in 1982, and defined the different populations of myoblasts appearing during development in birds and then in humans. Together, they demonstrated the impact of the limit in proliferation of the precursor cells on the regenerative capacity of human skeletal muscle, and their group developed models to evaluate the regenerative potential of skeletal muscle in vitro, measuring the telomeric erosion, and identified the involvement of a stress pathway in the proliferative arrest of muscle progenitors. A platform to produce human immortalized muscle cell lines was the successful result of this research, initiated with François Gros and W. E. Wright. The in vivo regenerative potential of human muscle cells was evaluated by injection into muscles of immunodeficient mice. Their group in collaboration with the clinical team of Professor Jean Lacau St-Guily and Professor Sophie Perié completed a successful autologous myoblast transplantation clinical trial for Oculo-pharyngeal muscular dystrophy. This common scientific career was made possible thanks to the precious and always benevolent support of François Gros. Gillian Butler-Browne a commencé à travailler sur le muscle à l’Institut Pasteur dans le laboratoire de François Gros en 1978. Elle a caractérisé le profil d’expression des différentes isoformes de myosine au cours du développement de l’homme et du rongeur. Vincent Mouly a rejoint ce laboratoire pour son doctorat en 1982, et a défini les différentes populations de myoblastes apparaissant au cours du développement chez les oiseaux puis chez l’homme. Ensemble, ils ont démontré l’impact de la limite de prolifération des cellules précurseurs sur la capacité de régénération du muscle squelettique humain, et leur groupe a développé des modèles pour évaluer le potentiel de régénération du muscle squelettique in vitro, en mesurant l’érosion télomérique, et a identifié l’implication d’une voie de stress dans l’arrêt de la prolifération des progéniteurs musculaires. Une plateforme de production de lignées de cellules musculaires humaines immortalisées a été le résultat fructueux de cette recherche, initiée avec François Gros et W. E. Wright. Le potentiel de régénération in vivo des cellules musculaires humaines a été évalué par injection dans des muscles de souris immunodéficientes. Leur groupe, en collaboration avec l’équipe clinique des professeurs Jean-Lacau-St Guily et Sophie Perié, a réalisé avec succès un essai clinique de transplantation autologue de myoblastes visant à traiter la dystrophie musculaire oculo-pharyngée. Cette carrière scientifique commune a été rendue possible par le soutien précieux et toujours bienveillant de François Gros.
2023-01-19 | [Nuclear aggregates in oculopharyngeal muscular dystrophy].
Oculopharyngeal muscular dystrophy (OPMD) is one of the diseases related to pathological expansions of trinucleotides. Its pathogenesis remains unclear although the presence of aggregates within the nuclei of the muscle fiber seems to play an important role. The basic research studies presented here help understand their composition and their deleterious role. These elements may result in new therapeutic avenues. Les agrégats nucléaires dans la dystrophie musculaire oculopharyngée. La dystrophie musculaire oculopharyngée est une des maladies en rapport avec des expansions pathologiques de triplets nucléotidiques. Sa physiopathologie est encore imparfaitement connue même si la présence d’agrégats au niveau des noyaux de la fibre musculaire semble jouer un rôle déterminant. Les travaux fondamentaux présentés ici permettent de mieux comprendre leur composition et leur rôle délétère. Autant d’éléments qui pourraient déboucher sur des voies thérapeutiques nouvelles.
2022-06-17 | A Systematic Review of Potential Immunotherapies Targeting PRAME in Retinoid Resistant Oral Potentially Malignant Disorders and Oral Cancer.
Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate the malignant transformation and progression of the lesion. Many agents have been attempted, but their cost inefficacy and inadequate outcomes posed a major hindrance in their successful adoption. Retinoid Based Therapy (RBT) though a cheap and effective treatment option, could not achieve much clinical usage because of variable responsiveness in clinical outcomes. Such clinical response variability may be attributed to the repression of retinoid receptors by Preferentially Expressed Antigen of Melanoma (PRAME) protein molecule. Therefore, in order to make RBT successful, targeting PRAME by various immunotherapies is an exciting area of research investigation. This review provides an insight into the various immunotherapeutic strategies targeting PRAME and their usefulness in retinoid-resistant OPMD and OC. Method of data collection: An exhaustive internet-based literature search following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was carried out in PUBMED and Google SCHOLAR database using terms 'Anti-PRAME' OR 'PRAME Immunotherapy' OR 'PRAME Vaccines' AND 'Cancer' AND 'Retinoid resistance'. Only articles in the English language with at least 1 citation, published in a journal with impact factor ≥ 1, having relevance to the context and availability of full text were considered. Results: After an initial search, 342 articles were yielded on the basis of inclusion criteria and, by reading the abstract and availability of full text, a total of 124 articles were selected. Further reading the full texts and considering articles from the references of the selected articles, a total of 65 articles were finally included in the review. Conclusion: Our analysis of the literature suggests that PRAME screening in OC and OPMDs prior to RBT should be done. In PRAME positive cases, approaches like PRAME based immunotherapy in the form of Cancer vaccine therapy [Acellular PRAME vaccine, PRAME pulsed Dendritic Cells (DC)]; Adoptive T Cell therapy/T Cell Receptor-T Cell therapy, Antibody therapy/Chimeric Antigen Receptor-T Cell therapy along with Presented antigen modulation Therapies employing histone deacetylase inhibitors and demethylation agents seem plausible. In the future, a combination therapy employing either PRAME vaccines or antibodies or Adoptive T cell Therapy and ATRA could be used in retinoid resistant OC and OPMDs.
2018-01-17 | Hydrogel biomaterials and their therapeutic potential for muscle injuries and muscular dystrophies
Muscular diseases such as muscular dystrophies and muscle injuries constitute a large group of ailments that manifest as muscle weakness, atrophy or fibrosis. Although cell therapy is a promising treatment option, the delivery and retention of cells in the muscle is difficult and prevents sustained regeneration needed for adequate functional improvements. Various types of biomaterials with different physical and chemical properties have been developed to improve the delivery of cells and/or growth factors for treating muscle injuries. Hydrogels are a family of materials with distinct advantages for use as cell delivery systems in muscle injuries and ailments, including their mild processing conditions, their similarities to natural tissue extracellular matrix, and their ability to be delivered with less invasive approaches. Moreover, hydrogels can be made to completely degrade in the body, leaving behind their biological payload in a process that can enhance the therapeutic process. For these reasons, hydrogels have shown great potential as cell delivery matrices. This paper reviews a few of the hydrogel systems currently being applied together with cell therapy and/or growth factor delivery to promote the therapeutic repair of muscle injuries and muscle wasting diseases such as muscular dystrophies.
proteins
2026-06-16 | Distinct roles of IDR and CCD domains control PABPN1 aggregation and enable therapeutic rescue
Abstract PABPN1 is a multifunctional protein whose expression is tightly regulated to maintain cellular homeostasis. PABPN1 dysregulation contributes to both common acquired diseases, such as bladder cancer, and rare inherited disorders, including oculopharyngeal muscular dystrophy (OPMD). In OPMD, PABPN1 forms insoluble aggregates that reduce its functional levels, leading to genome-wide shifts in alternative polyadenylation (APA) at 3′-UTRs and disruption of mRNA metabolism, including nuclear export and translation. OPMD is caused by a short alanine expansion at the N-terminus of PABPN1 within an intrinsically disordered region (IDR) followed by a coiled-coil domain (CCD). How these domains contribute to PABPN1 function and aggregation remains unclear. Here, we show that the N-terminal IDR promotes aggregation and modulates protein-protein interactions with longer IDRs suppressing interaction between PABPN1 and its binding partners. We further demonstrate that the CCD has dual functions: its N-terminal domain dictates PABPN1 stability, whereas its C-terminal domain enhances the PABPN1 interactome. We identified a naturally occurring variant lacking exon 1 encoding the IDR and the CCD N-terminal domain (named trPAB). That variant forms a stable, non-aggregating protein isoform. Interactome analysis and structural modeling indicate improved molecular function by restoring PABPN1 activity, APA profiles, and cellular phenotypes in OPMD and bladder cancer models. Importantly, delivery of trPAB via Adeno-associated viral vector in an OPMD mouse model improves muscle histopathology, supporting its potential as a therapeutic strategy. A mechanistic basis of a novel gene therapy approach for OPMD Top panel: A schematic presentation of three PABPN1 variant functional states. Left: the normal full-length protein interacts with key RNA binding protein (RBP) partners supporting normal cellular function. Middle: A pathogenic full-length alanine-expanded PABPN1 leads to protein aggregation, resulting in limited interactors, dysfunctional complexes and impaired cellular processes. Right: a truncated natural variant (trPAB), not associated with OPMD pathology, shows enhanced stability and reduced aggregation, suggesting a potential protective or “super functional” profile. The bottom panel translates these mechanistic insights into therapeutic strategy. In cell models, expression of trPAB is associated with reduced protein aggregation, restoration of normal cellular function, and improved myogenesis. These effects are recapitulated in a relevant animal model of OPMD, where trPAB treatment leads to decreased aggregation, functional recovery, and reversal of muscle atrophy. Our study supports the rationale for leveraging a stabilized PABPN1 variant as a novel gene therapy approach to counteract aggregation-driven pathology in OPMD. Highlights The central coiled-coil domain (CCD) of PABPN1 has two opposing functions: its N-terminal region stabilizes the protein, while its C-terminal region promotes stability but hampers aggregation. At the N-terminus, an intrinsically disordered region (IDR) acts as a gatekeeper for protein interactions. The alanine tract, including its pathogenic expansion, restricts this interactome, limiting PABPN1 binding capacity. We identified a naturally occurring PABPN1 isoform, trPAB, which lacks exon 1, including the IDR and the N-terminal portion of the CCD. trPAB forms a stable and functional protein and exerts beneficial effects in muscle cells. Functionally, trPAB rescues key cellular phenotypes in bladder cancer cells and reverses nuclear aggregation and muscle atrophy in a mouse model of OPMD.
2025-05-23 | Oculopharyngeal muscular dystrophy (OPMD) associated alanine expansion impairs the function of the nuclear polyadenosine RNA binding protein PABPN1 as revealed by proximity labeling and comparative proteomics
Abstract Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disease caused by modest alanine expansion at the amino terminus of the nuclear polyadenosine RNA binding protein PABPN1. PABPN1 is expressed ubiquitously and is involved in multiple steps in RNA processing including optimal cleavage and polyadenylation, polyadenylation signal selection, and export of polyadenylated RNAs from the nucleus. Expanded PABPN1 forms aggregates in a subset of muscle nuclei, but PABPN1 levels are paradoxically low in muscle compared to other tissues. Despite several studies in model systems and patient tissues, it remains unclear whether alanine expansion directly impairs PABPN1 function. The molecular mechanisms leading to OPMD pathology are poorly understood. Here we used a proximity labeling approach to better understand the effect of alanine expansion on PABPN1 function in a cell culture model of skeletal muscle. To avoid the confounding factor of overexpression, PABPN1 constructs containing a carboxy-terminal TurboID tag were expressed in skeletal myotubes at near native levels using an inducible promoter. Although non-expanded PABPN1-TurboID was able to complement RNA export and myoblast differentiation defects caused by deficiency of endogenous PABPN1, alanine expanded PABPN1-TurboID was not. Comparative proteomics revealed increased interaction between expanded PABPN1 and RNA splicing and polyadenylation machinery and follow-up studies identified a dominant negative effect on RNA export in differentiated myotubes. These data indicate that alanine expansion can impair PABPN1 function regardless of the presence of wild type PABPN1 and support a model wherein both loss function and dominant negative effects of expanded PABPN1 contribute to OPMD pathology. Author summary Oculopharyngeal muscular dystrophy (OPMD) is a late onset muscle disease that, unlike other muscular dystrophies, causes progressive weakness primarily in muscles of the face and head. OPMD is most commonly inherited in a dominant fashion and is caused by small expansions in the gene encoding the RNA binding protein PABPN1. Despite the fact that PABPN1 is expressed ubiquitously and contributes to multiple steps in RNA processing, its expansion causes disease almost exclusively in skeletal muscle. The precise molecular events leading to OPMD disease onset have been difficult to characterize as it is challenging to separate functions expanded versus non-expanded PABPN1 in muscle without the confounding factor of overexpressing tagged fusion proteins. Here we fused expanded and non-expanded PABPN1 to the modified biotin ligase TurboID to label proximal proteins. PABPN1-TurboID fusions were expressed in a cell culture model of skeletal muscle at near-native levels. Using these constructs, we discovered that expanded PABPN1 is less functional than non-expanded PABPN1 and causes dominant negative effects on some PABPN1 functions. These findings support a model where both loss of function and dominant negative effects contribute to the molecular pathology of OPMD.
2022-07-20 | Botulinum toxin treatment improves dysphagia in patients with oculopharyngeal muscular dystrophy and sporadic inclusion body myositis.
Dysphagia can be troublesome in sporadic inclusion body myositis (sIBM) and oculopharyngeal muscular dystrophy (OPMD), but no established treatment exists. Cricopharyngeal muscle botulinum toxin injection has at case level been reported to be effective. We evaluated safety and efficacy of botulinum toxin injections in the cricopharyngeal muscle in patients with dysphagia due to sIBM or OPMD. Participants were included from our outpatient clinic. Cricopharyngeal constriction was confirmed by laryngoscopy. After EMG confirmation of needle placement in the cricopharyngeal muscle, botulinum toxin A was injected in awake patients. An individualized dose of 5-10 units of botulinum toxin A was applied initially and titrated up a maximum of 3 times. Outcome measures were change in dysphagia questionnaire, timed cold-water swallow test and subjective dysphagia status (worse, unchanged, improved). Due to the need for individualized dosing and a limited number of available patients, an uncontrolled, un-blinded design was used. Thirteen patients, 3 with OPMD, received at least 1 injection. In the dysphagia questionnaire, all but 2 subjects, none with subjective worsening, improved (p < 0.001). Subjectively, seven felt an improvement, 4 no change and 2 a worsening. No overall change was seen the timed cold-water swallow test. No serious adverse events were observed. Botulinum toxin injection of the cricopharyngeal muscle in patients with OPMD and sIBM had a beneficial effect on dysphagia in most of the treated patients. Two of 13 patients experienced a temporary worsening not reflected in dysphagia score. Limitations are the un-blinded and un-randomized design and subjective assessments methods. EudraCT-number: 2014-002210-23.
2017-09-12 | Effects of botulinum toxin injections in the cricopharyngeal muscle of OPMD and IBM myopathies with dysphagia
Certain myopathies have dysphagia as a pronounced and very troublesome symptom, but no established treatment exists. Botulinum toxin injection in the cricopharyngeal muscle has at case level been reported to be effective. To systematically evaluate the safety and efficacy of injections of botulinum toxin in the cricopharyngeal muscle in patients with dysphagia due to inclusion body myositis (IBM) or oculopharyngeal muscular dystrophy (OPMD). Patients with confirmed diagnoses of IBM or OPMD and dysphagia were included if no other cause for dysphagia was present, and if dysphagia, assessed by a timed water swallow test, a dysphagia questionnaire and by meal registration, was pronounced. Additional baseline registration included body weight, number of pneumonia episodes, muscle strength and enzyme measurements. Initially, laryngoscopia was performed followed by needle electromyography to confirm activity in the cricopharyngeal muscle and to establish needle placement. Botulinum toxin was then injected through the hollow EMG needle. An individualized dose of 5–10 units was applied bilaterally the first time and the dose was then titrated up with at least 12 weeks' intervals. Suspected side effects were noted at each visit. Outcome measures were change in timed water swallowing test, dysphagia questionnaire and meal registration. 12 subjects were included, 3 with OPMD. Preliminary results from 6 subjects show that 4 felt a clear improvement, whereas 2 were excluded due to that a worsening was suspected based on subjective observations and worsening in the meal registration assessment. In the dysphagia questionnaire, however, every single subject improved (p < 0.001). No overall change was seen in the meal registration assessment and the timed water swallow test. Preliminary results suggest a positive effect on dysphagia of cricopharyngeal botulinum toxin in patients with OPMD and IBM.
2014-11-03 | Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region‐dependent manner
Key points Millions of elderly individuals have dysphagia, a debilitating and life‐threatening condition in which the ability to swallow is impaired. Several muscles surround the three regions of the pharynx, which are essential for proper swallowing, yet the effects of ageing and disease on these muscles are not well understood. We demonstrate that the fibre size of murine pharyngeal muscles is differentially affected by ageing and muscular dystrophy depending on their location within the pharynx. Using a mouse model of an age‐associated dysphagic disease (oculopharyngeal muscular dystrophy), we show that overexpression of wild‐type polyadenylate binding nuclear protein 1 in muscle tissue prevents age‐related dysphagia and age‐related muscle atrophy of laryngopharyngeal muscles. These results demonstrate that mice are an excellent model for studying mechanisms of ageing and disease on pharyngeal muscle physiology, and such studies could lead to new therapies for individuals with dysphagia. Abstract The inability to swallow, or dysphagia, is a debilitating and life‐threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild‐type mice depending on the particular muscle analysed. Furthermore, wild‐type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild‐type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild‐type A10 PABPN1 was protective against age‐related muscle atrophy in the laryngopharynx and prevented the development of age‐related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region‐dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia.
small molecules
2026-08-06 | Direct Observationof Structural Unraveling in PABPN1Polyalanine Expansions
Abstract Above-threshold homorepeat expansions promote alternative conformations and irreversible aggregation, driving the malfunction of numerous disease-associated proteins. A detailed understanding of the structural remodeling events in pathogenic mutants enables the identification of key elements determining aberrant structure formation. Here, we describe in high resolution the structural transitions in Poly(A) Binding Protein Nuclear 1 (PABPN1), in which polyalanine expansions beyond a +1 single additional residue cause Oculopharyngeal Muscular Dystrophy (OPMD). PABPN1’s polyalanine tract in its wild-type (containing 10 consecutive alanine residues) and +1 and +8 variants populate alternative polymorphs, with α-helical conformations being increasingly favored and rigid upon expansion. Spontaneous slow unfolding was observed across variants in real time by Nuclear Magnetic Resonance (NMR) spectroscopy, indicating that increased dynamics at the C-terminal end of the polyalanine helix emerges as an early unfolding event associated with functional impairment. Our data help to define key mechanistic features in pathogenic misfunction induced by homorepeat expansions and identify specific structural motifs as potential targets for fragment-based binders to restore protein functionality in polyalanine expansion disorders.
2026-07-28 | Impaired Myogenic Differentiation Is a Shared Feature Across Genetic Myopathies.
There is a shared hallmark of defective differentiation across genetic myopathies, a process that has been extensively described in Duchenne muscular dystrophy and also observed in Emery-Dreifuss muscular dystrophy. In this article, we broaden the discussion on myopathies associated with differentiation defects, examining their implications in less characterized muscle conditions that can have onset in adulthood, including facioscapulohumeral muscular dystrophy (FSHD), oculopharyngeal muscular dystrophy (OPMD), and myotonic dystrophies (DM), as well as myopathies caused by genetic variants in FHL1, GNE, DES, CAPN3, and members of the HNRNP family. Muscle damage can result from injury, exercise, or disease, necessitating a highly coordinated repair process to restore normal strength and function. Resident satellite cells are activated, differentiate, and fuse with the damaged tissue to facilitate this repair. This overview emphasizes the importance of muscle differentiation in the pathogenesis of myopathies with diverse etiologies and a broad range of underlying molecular mechanisms. These insights highlight differentiation as a potential convergent therapeutic target.
2026-04-30 | Molecular and therapeutic effects of bioactive compounds-incorporated mucoadhesive buccal patch targeting oral potentially malignant disorders.
Oral potentially malignant disorders (OPMD) are associated with high risk of progression to oral squamous cell carcinoma (OSCC) and remain difficult to manage, due to limited effective localized therapies, underscoring the urgent need for novel, targeted drug delivery systems. A mucoadhesive buccal patch loaded bioactive components such as isotretinoin, bromelain, and limonene (IBL patch) was fabricated and evaluated for its anticancer potential against OPMD-associated OSCC. The cytotoxic study demonstrated that the IBL patch significantly reduced CAL-27 cells viability and found IC50 value around 650 μg/mL, while exhibiting minimal cytotoxicity toward human gingival fibroblast (HGF) cells, indicating selective anticancer activity. In comparison to HGF cells, the IBL patch significantly reduced the migration and invasion of CAL-27 cells. Colony formation assays further confirmed that the IBL patch significantly suppressed the long-term proliferative and clonogenic potential of CAL-27 cells, without affecting HGF cells division. Genotoxicity analysis revealed increased micronucleus formation in CAL-27 cells, suggesting DNA damage-mediated apoptotic induction. Then IBL patch showed molecular effects by suppressing EMT and fibrosis associated TGF-β/SMAD signaling, inhibiting inflammatory (NF-κB), Wnt/β-Catenin pathways and Cytokeratin 17 (CK-17) and restoring epithelial identity through E-Cadherin and CK-18 upregulation. Furthermore, pathway analysis in both monolayer and co-culture inflammatory models demonstrated that the IBL patch effectively suppressed LPS-induced inflammatory markers, including TGF-β, MMP-2, IL-6, and TNF-α expression. Oral acute toxicity testing (OECD 423) confirmed safety of the IBL patch, with no mortality or adverse effects up to 2000 mg/kg (LD₅₀ > 2000 mg/kg; GHS Category 5). Collectively, these findings highlights that the IBL mucoadhesive buccal patch has therapeutic potential against OPMD and controlling pathological epithelial remodeling.
2026-04-02 | Cysteine proteases in oral potentially malignant disorders: Molecular drivers, diagnostic signatures, and therapeutic opportunities.
Cysteine proteases are crucial enzymes regulating protein turnover, apoptosis, signalling, and tissue remodelling, and have emerged as important regulators of the oral epithelial microenvironment with increasing evidence implicating them in the progression of oral potentially malignant disorders (OPMDs) and their potential contribution to malignant transformation toward oral squamous cell carcinoma (OSCC). Dysregulated expression of these enzymes influences key molecular pathways, notably NF-κB, MAPK, protease-activated receptor (PAR) signalling, and apoptotic cascades, although the extent to which individual cysteine proteases act as primary drivers, facilitators of tumour-associated microenvironmental remodelling, or biomarkers of disease progression remains incompletely defined, which govern extracellular matrix remodelling, inflammation, proliferation, migration, and immune evasion, processes associated with malignant progression. Their diagnostic potential is evident through distinct expression patterns in saliva and tissue, suggesting potential utility as adjunct salivary biomarkers for early detection; however, their diagnostic performance relative to established approaches such as toluidine blue staining, autofluorescence imaging, and cytopathological assessment remains to be systematically evaluated. On the therapeutic front, approaches such as selective inhibitors, plant-derived proteases, prodrugs, and multifunctional theranostic agents have been explored experimentally for modulating inflammation, fibrosis, and tumour invasion, while innovative drug delivery strategies aim to increase specificity and reduce systemic toxicity. Nevertheless, most cysteine-protease-targeted interventions remain at preclinical or early translational stages, and clinical validation in oral diseases is currently limited. However, challenges including resistance mechanisms, lack of absolute selectivity, and potential off-target effects necessitate refined computational and experimental strategies for rational inhibitor design. Furthermore, the relative contribution of individual cysteine proteases across different OPMD subtypes remains insufficiently characterized. Future advances lie in validating protease-based biomarkers across diverse populations and embedding them into personalized medicine frameworks.
2026-02-18 | GGC repeat expansions within new open reading frames are translated into toxic polyglycine proteins in oculopharyngodistal myopathy.
A total of 3-6% human genome is composed of microsatellite sequences, which are short DNA elements composed of two to six nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as noncoding, which raises questions about their pathogenicity. Here we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without oculopharyngeal myopathy leukoencephalopathy are located within previously unrecognized open reading frames (ORFs), resulting in their translation into new polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting the expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet-unrecognized small ORFs.
antibodies
2023-09-29 | Generation and Immuno-inflammatory Checkpoints in Oral Cavity Cancers
Oral malignancies are responsible for a considerable portion of cancer-related deaths worldwide. Even though survival rates have increased recently, new treatments are being explored to slow the advancement of the disease and enhance outcomes, especially in cases of oral cavity squamous cell carcinoma (OSCC) and oral potentially malignant diseases (OPMDs). Immunotherapy is a novel therapeutic approach that targets immune checkpoint molecules such as programmed cell death protein-1 (PD-1) and its ligand programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4, lymphocyte-activated gene 3, and T cell immunoglobulin mucin 3 in order to enhance the host’s immune response against malignancies and impede the growth and metastasis of cancer cells. Accordingly, a systematic review was performed by scanning five databases for keywords related to immune checkpoint inhibitors, along with oral malignancies, oral pathologies, and OPMDs, in order to describe the current state of their use and efficacy in these disorders. For this purpose, 644 unique publications published between 2004 and 2019 were found, 76 of which were judged to be appropriate for the study and produced 8826 samples. PD-1 and PD-L1 are expressed in most OPMD and OSCC samples, and their expression is associated with worse survival rates and greater rates of progression. Two immunotherapy drugs targeting PD-1, namely, pembrolizumab and nivolumab, have been demonstrated to enhance disease outcomes and increase survival rates, especially when combined with radiation or chemotherapy. Despite the equivocal nature of the available data, there is support for the prognostic and predictive usefulness of immune checkpoint molecules, notably PD-L1, and multiple studies support the useful use of immune checkpoint inhibitors in the management of OSCC.
2022-11-22 | Systemic Delivery of a Monoclonal Antibody to Immunologically Block Myostatin in the A17 Mouse Model of OPMD.
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset rare muscle disease affecting approximately 1 in 80,000 individuals worldwide. However, it can affect as much as 1:600 individuals in some populations due to a strong founder effect. The muscle pathology is characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and limb weakness at later stages of disease progression. The genetic defect is associated with significant fibrotic deposition and atrophy in affected muscles. No treatments are available to cure the disease. Only surgical techniques to correct ptosis and swallowing are currently possible, though they carry a risk of recurrence. Myostatin is a negative regulator of muscle growth, and several strategies to downregulate its expression have been developed with the aim of improving muscle mass and strength in muscular pathologies. We recently showed that weekly systemic treatment of the A17 murine model of OPMD with a monoclonal antibody for myostatin improves body and muscle mass, increases muscle strength, and reduces muscle fibrosis. Here, we describe the methodology for repeated intraperitoneal delivery of myostatin antibody in the murine model. Furthermore, we detail the most relevant analyses to assess histopathological and functional improvements of this treatment in this mouse model.
2020-03-05 | Inhibition of Myostatin Reduces Collagen Deposition in a Mouse Model of Oculopharyngeal Muscular Dystrophy (OPMD) With Established Disease
Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscle disease presented by ptosis, dysphagia, and limb weakness. Affected muscles display increased fibrosis and atrophy, with characteristic inclusion bodies in the nucleus. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to improve symptoms in models of muscular dystrophy.We systemically administered a monoclonal antibody to block myostatin in the A17 mouse model of OPMD at 42 weeks of age. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which serum and histological analyses were performed on muscle samples.The administration of the antibody resulted in a significant decrease in serum myostatin and collagen deposition in muscles. However, minimal effects on body mass, muscle mass and myofiber diameter, or the density of intranuclear inclusions (INIs) (a hallmark of disease progression of OPMD) were observed.This study demonstrates that inhibition of myostatin does not revert muscle atrophy in a mouse model with established OPMD disease, but is effective at reducing observed histological markers of fibrosis in the treated muscles.
2019-05-07 | Inhibition of myostatin improves muscle atrophy in oculopharyngeal muscular dystrophy (OPMD)
Abstract Background Oculopharyngeal muscular dystrophy (OPMD) is a late‐onset muscle disease affecting one per 80 000 of the general population characterized by profound dysphagia and ptosis, and limb weakness at later stages. Affected muscles are characterized by increased fibrosis and atrophy. Myostatin is a negative regulator of muscle mass, and inhibition of myostatin has been demonstrated to ameliorate symptoms in dystrophic muscles. Methods In this study, we performed a systemic delivery of a monoclonal antibody to immunologically block myostatin in the A17 mouse model of OPMD. The mice were administered a weekly dose of 10 mg/kg RK35 intraperitonially for 10 weeks, following which histological analyses were performed on the samples. Results This treatment significantly ( P < 0.01) improved body mass (11%) and muscle mass (for the tibialis anterior and extensor digitorum longus by 19% and 41%) in the A17 mice treated with RK35 when compared to saline controls. Similarly, a significantly ( P < 0.01) increased muscle strength (18% increase in maximal tetanic force) and myofibre diameter (17% and 44% for the tibialis anterior and extensor digitorum longus), and reduced expression of markers of muscle fibrosis (40% reduction in area of expression), was also observed. No change in the density of intranuclear inclusions (a hallmark of disease progression of OPMD) was however observed. Conclusions Our study supports the clinical translation of such antibody‐mediated inhibition of myostatin as a treatment of OPMD. This strategy has implications to be used as adjuvant therapies with gene therapy based approaches, or to stabilize the muscle prior to myoblast transplantation.
2010-03-10 | Structural basis for a PABPN1 aggregation‐preventing antibody fragment in OPMD
Oculopharyngeal muscular dystrophy is caused by small alanine expansions in polyadenylate binding protein nuclear 1 (PABPN1) protein resulting in its intranuclear accumulation in skeletal muscle. 3F5 llama antibody specifically interferes with the PABPN1 aggregation process in vitro and in vivo. To understand the structural basis for its epitope recognition we mapped the binding interface of 3F5 with PABPN1 and provide a structural model of the 3F5-PABPN1 complex. We show that 3F5 complementarity determining regions create a cavity in which PABPN1 alpha-helix domain resides by involving critical residues previously implicated in the aggregation process. These results may increase our understanding of the PABPN1 aggregation mechanism and the therapeutic potential of 3F5.
oligonucleotides
2026-01-01 | THE MICROECOLOGICAL AETIOLOGY OF ORAL CANCER: DECIPHERING THE ROLE OF THE ORAL MICROBIOME IN THE MALIGNANT TRANSFORMATION OF OPMDS
The malignant transformation of oral potentially malignant disorders (OPMDs) into oral squamous cell carcinoma (OSCC) has traditionally been viewed through the narrow lens of host genomic instability and cumulative environmental mutagenesis. However, the diagnostic paradigm is currently undergoing a profound shift. Advanced multi-omics sequencing has unveiled a vast, highly active oral microecosystem that does not merely colonise neoplastic tissue opportunistically, but actively orchestrates the aetiopathogenesis of the tumour. This review exhaustively examines the transition from microbial haemostasis to pathogenic dysbiosis within OPMDs. By mapping the specific mechanisms through which keystone periopathogens—namely Fusobacterium nucleatumand Porphyromonas gingivalis—induce the epithelial-mesenchymal transition (EMT), hyperactivate inflammatory signalling cascades, and subvert local immune surveillance, this manuscript provides a comprehensive molecular framework. Integrating microbial landscaping into routine oral pathology offers profound new avenues for predicting malignant transformation and designing targeted microecological therapies.
2025-09-01 | 564PDevelopment of an antisense oligonucleotide therapy for oculopharyngeal muscular dystrophy using iPSC-derived myocytes
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder prevalent in French Canadians (1:1000). It causes progressive ptosis, dysphagia, and proximal weakness, with no disease-modifying therapy available. OPMD results from GCG expansions in the PABPN1 gene, with patients commonly having 13-15 repeats versus 10 in healthy individuals. We aim to develop a cellular OPMD model and evaluate antisense oligonucleotides (ASOs) as a therapy by 1) Generating CRISPR-edited induced pluripotent stem cells (iPSCs) with 13 GCN repeats in PABPN1, and 2) Differentiating these cells into myocytes for investigating candidate ASOs. The expanded GCG repeats will be introduced into KOLF2.1J iPSCs by using a pair of single guide RNAs combined with a Cas9 nickase. After validation, cells will be differentiated into myocytes using PiggyBac-Tet-On-MyoD1. Myocytes will be characterized by immunofluorescence for myogenic markers and PABPN1 pathology. We will test phosphorothioate-modified ASOs with LNA or 2′-MOE chemistry targeting expanded repeats to reduce mutant PABPN1 while preserving wild-type levels. Preliminary experiments showed that the designed guide RNAs created a staggered double-strand break in the PABPN1 gene, which is ideal to favor homology-directed repair while minimizing off-target effects. In addition, wild type iPSCs were successfully differentiated into homogeneous myotubes culture expressing myosin filaments. We anticipate creating a model displaying PABPN1 nuclear aggregates and identifying ASOs that selectively target the expanded allele while preserving wild-type PABPN1 function, essential for normal muscle physiology. This project establishes a foundation for developing a disease-modifying therapy for OPMD through a human cellular model and allele-specific ASOs, potentially leading to clinical translation for this untreatable condition.
2023-08-09 | Oculopharyngeal muscular dystrophy mutations link the RNA-binding protein HNRNPQ to autophagosome biogenesis.
Autophagy is an intracellular degradative process with an important role in cellular homeostasis. Here, we show that the RNA binding protein (RBP), heterogeneous nuclear ribonucleoprotein Q (HNRNPQ)/SYNCRIP is required to stimulate early events in autophagosome biogenesis, in particular the induction of VPS34 kinase by ULK1-mediated beclin 1 phosphorylation. The RBPs HNRNPQ and poly(A) binding protein nuclear 1 (PABPN1) form a regulatory network that controls the turnover of distinct autophagy-related (ATG) proteins. We also show that oculopharyngeal muscular dystrophy (OPMD) mutations engender a switch from autophagosome stimulation to autophagosome inhibition by impairing PABPN1 and HNRNPQ control of the level of ULK1. The overexpression of HNRNPQ in OPMD patient-derived cells rescues the defective autophagy in these cells. Our data reveal a regulatory mechanism of autophagy induction that is compromised by PABPN1 disease mutations, and may thus further contribute to their deleterious effects.
2023-08-03 | Tau-RNA complexes inhibit microtubule polymerization and drive disease-relevant conformation change.
Alzheimer's disease and related disorders feature neurofibrillary tangles and other neuropathological lesions composed of detergent-insoluble tau protein. In recent structural biology studies of tau proteinopathy, aggregated tau forms a distinct set of conformational variants specific to the different types of tauopathy disorders. However, the constituents driving the formation of distinct pathological tau conformations on pathway to tau-mediated neurodegeneration remain unknown. Previous work demonstrated RNA can serve as a driver of tau aggregation, and RNA associates with tau containing lesions, but tools for evaluating tau/RNA interactions remain limited. Here, we employed molecular interaction studies to measure the impact of tau/RNA binding on tau microtubule binding and aggregation. To investigate the importance of tau/RNA complexes (TRCs) in neurodegenerative disease, we raised a monoclonal antibody (TRC35) against aggregated tau/RNA complexes. We showed that native tau binds RNA with high affinity but low specificity, and tau binding to RNA competes with tau-mediated microtubule assembly functions. Tau/RNA interaction in vitro promotes the formation of higher molecular weight tau/RNA complexes, which represent an oligomeric tau species. Coexpression of tau and poly(A)45 RNA transgenes in Caenorhabditis elegans exacerbates tau-related phenotypes including neuronal dysfunction and pathological tau accumulation. TRC35 exhibits specificity for Alzheimer's disease-derived detergent-insoluble tau relative to soluble recombinant tau. Immunostaining with TRC35 labels a wide variety of pathological tau lesions in animal models of tauopathy, which are reduced in mice lacking the RNA binding protein MSUT2. TRC-positive lesions are evident in many human tauopathies including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration and Pick's disease. We also identified ocular pharyngeal muscular dystrophy as a novel tauopathy disorder, where loss of function in the poly(A) RNA binding protein (PABPN1) causes accumulation of pathological tau in tissue from post-mortem human brain. Tau/RNA binding drives tau conformational change and aggregation inhibiting tau-mediated microtubule assembly. Our findings implicate cellular tau/RNA interactions as modulators of both normal tau function and pathological tau toxicity in tauopathy disorders and suggest feasibility for novel therapeutic approaches targeting TRCs.
2022-05-02 | Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy.
Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics.
other
2024-10-18 | Sequential development of parkinsonism in two patients with oculopharyngodistal type myopathy in GIPC1-related repeat expansion disorder.
A heterozygous CGG repeat expansion in 5' untranslated region (5' UTR) of GIPC1 is one of the causative factors of oculopharyngodistal myopathy (OPDM), an adult-onset hereditary muscle disease characterized by progressive ptosis, ophthalmoplegia, and facial, bulbar, and distal limb muscle weakness. CGG repeat expansion in GIPC1 has also been reported to be associated with Parkinson's disease, but these patients did not exhibit myopathic symptoms. We experienced two unrelated cases of oculopharyngeal type myopathy with CGG repeat expansion in GIPC1 presenting parkinsonism after exhibiting myopathic symptoms. Both cases showed p62-positive intranuclear inclusions in the skin, similar to those in NOTCH2NLC-related disorders. Our cases suggest that GIPC1-related repeat expansions may be associated with a broad spectrum and tissue-differential neuromuscular manifestations, indicating a common mechanism between OPDM2 and other CGG-repeat expansion diseases. It is important to note OPDM2 patients' central neurological symptoms, as myopathic symptoms may obscure central nervous system manifestations.
2024-04-01 | Our journey with François Gros.
Gillian Butler-Browne began working on muscle at the Institut Pasteur in the laboratory of François Gros in 1978. She characterized the expression profile of different myosin isoforms during both human and rodent development. Vincent Mouly joined this laboratory for his PhD in 1982, and defined the different populations of myoblasts appearing during development in birds and then in humans. Together, they demonstrated the impact of the limit in proliferation of the precursor cells on the regenerative capacity of human skeletal muscle, and their group developed models to evaluate the regenerative potential of skeletal muscle in vitro, measuring the telomeric erosion, and identified the involvement of a stress pathway in the proliferative arrest of muscle progenitors. A platform to produce human immortalized muscle cell lines was the successful result of this research, initiated with François Gros and W. E. Wright. The in vivo regenerative potential of human muscle cells was evaluated by injection into muscles of immunodeficient mice. Their group in collaboration with the clinical team of Professor Jean Lacau St-Guily and Professor Sophie Perié completed a successful autologous myoblast transplantation clinical trial for Oculo-pharyngeal muscular dystrophy. This common scientific career was made possible thanks to the precious and always benevolent support of François Gros. Gillian Butler-Browne a commencé à travailler sur le muscle à l’Institut Pasteur dans le laboratoire de François Gros en 1978. Elle a caractérisé le profil d’expression des différentes isoformes de myosine au cours du développement de l’homme et du rongeur. Vincent Mouly a rejoint ce laboratoire pour son doctorat en 1982, et a défini les différentes populations de myoblastes apparaissant au cours du développement chez les oiseaux puis chez l’homme. Ensemble, ils ont démontré l’impact de la limite de prolifération des cellules précurseurs sur la capacité de régénération du muscle squelettique humain, et leur groupe a développé des modèles pour évaluer le potentiel de régénération du muscle squelettique in vitro, en mesurant l’érosion télomérique, et a identifié l’implication d’une voie de stress dans l’arrêt de la prolifération des progéniteurs musculaires. Une plateforme de production de lignées de cellules musculaires humaines immortalisées a été le résultat fructueux de cette recherche, initiée avec François Gros et W. E. Wright. Le potentiel de régénération in vivo des cellules musculaires humaines a été évalué par injection dans des muscles de souris immunodéficientes. Leur groupe, en collaboration avec l’équipe clinique des professeurs Jean-Lacau-St Guily et Sophie Perié, a réalisé avec succès un essai clinique de transplantation autologue de myoblastes visant à traiter la dystrophie musculaire oculo-pharyngée. Cette carrière scientifique commune a été rendue possible par le soutien précieux et toujours bienveillant de François Gros.
2023-01-19 | [Nuclear aggregates in oculopharyngeal muscular dystrophy].
Oculopharyngeal muscular dystrophy (OPMD) is one of the diseases related to pathological expansions of trinucleotides. Its pathogenesis remains unclear although the presence of aggregates within the nuclei of the muscle fiber seems to play an important role. The basic research studies presented here help understand their composition and their deleterious role. These elements may result in new therapeutic avenues. Les agrégats nucléaires dans la dystrophie musculaire oculopharyngée. La dystrophie musculaire oculopharyngée est une des maladies en rapport avec des expansions pathologiques de triplets nucléotidiques. Sa physiopathologie est encore imparfaitement connue même si la présence d’agrégats au niveau des noyaux de la fibre musculaire semble jouer un rôle déterminant. Les travaux fondamentaux présentés ici permettent de mieux comprendre leur composition et leur rôle délétère. Autant d’éléments qui pourraient déboucher sur des voies thérapeutiques nouvelles.
2022-06-17 | A Systematic Review of Potential Immunotherapies Targeting PRAME in Retinoid Resistant Oral Potentially Malignant Disorders and Oral Cancer.
Backgound and objective: Early chemoprevention in Oral Potentially Malignant Disorders (OPMDs) and Oral Cancer (OC) has been extensively researched in order to mitigate the malignant transformation and progression of the lesion. Many agents have been attempted, but their cost inefficacy and inadequate outcomes posed a major hindrance in their successful adoption. Retinoid Based Therapy (RBT) though a cheap and effective treatment option, could not achieve much clinical usage because of variable responsiveness in clinical outcomes. Such clinical response variability may be attributed to the repression of retinoid receptors by Preferentially Expressed Antigen of Melanoma (PRAME) protein molecule. Therefore, in order to make RBT successful, targeting PRAME by various immunotherapies is an exciting area of research investigation. This review provides an insight into the various immunotherapeutic strategies targeting PRAME and their usefulness in retinoid-resistant OPMD and OC. Method of data collection: An exhaustive internet-based literature search following PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines was carried out in PUBMED and Google SCHOLAR database using terms 'Anti-PRAME' OR 'PRAME Immunotherapy' OR 'PRAME Vaccines' AND 'Cancer' AND 'Retinoid resistance'. Only articles in the English language with at least 1 citation, published in a journal with impact factor ≥ 1, having relevance to the context and availability of full text were considered. Results: After an initial search, 342 articles were yielded on the basis of inclusion criteria and, by reading the abstract and availability of full text, a total of 124 articles were selected. Further reading the full texts and considering articles from the references of the selected articles, a total of 65 articles were finally included in the review. Conclusion: Our analysis of the literature suggests that PRAME screening in OC and OPMDs prior to RBT should be done. In PRAME positive cases, approaches like PRAME based immunotherapy in the form of Cancer vaccine therapy [Acellular PRAME vaccine, PRAME pulsed Dendritic Cells (DC)]; Adoptive T Cell therapy/T Cell Receptor-T Cell therapy, Antibody therapy/Chimeric Antigen Receptor-T Cell therapy along with Presented antigen modulation Therapies employing histone deacetylase inhibitors and demethylation agents seem plausible. In the future, a combination therapy employing either PRAME vaccines or antibodies or Adoptive T cell Therapy and ATRA could be used in retinoid resistant OC and OPMDs.
2018-01-17 | Hydrogel biomaterials and their therapeutic potential for muscle injuries and muscular dystrophies
Muscular diseases such as muscular dystrophies and muscle injuries constitute a large group of ailments that manifest as muscle weakness, atrophy or fibrosis. Although cell therapy is a promising treatment option, the delivery and retention of cells in the muscle is difficult and prevents sustained regeneration needed for adequate functional improvements. Various types of biomaterials with different physical and chemical properties have been developed to improve the delivery of cells and/or growth factors for treating muscle injuries. Hydrogels are a family of materials with distinct advantages for use as cell delivery systems in muscle injuries and ailments, including their mild processing conditions, their similarities to natural tissue extracellular matrix, and their ability to be delivered with less invasive approaches. Moreover, hydrogels can be made to completely degrade in the body, leaving behind their biological payload in a process that can enhance the therapeutic process. For these reasons, hydrogels have shown great potential as cell delivery matrices. This paper reviews a few of the hydrogel systems currently being applied together with cell therapy and/or growth factor delivery to promote the therapeutic repair of muscle injuries and muscle wasting diseases such as muscular dystrophies.
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Drug Discovery Landscape
3 orphan drug designations for Oculopharyngeal muscular dystrophy.
3 orphan drug designations for Oculopharyngeal muscular dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
genetically modified, non-self replicating Adeno-Associated Virus serotype 9 expressing shRNA to knock down mutant PABP1 as well as a codon optimized, shRNA-insensitive, wildtype PABN1 | gene therapies | FDA | Benitec Biopharma Limited | |
Genetically modified adeno-associated viral vector serotype 9 expressing shRNA as well as a codon-optimized shRNA-insensitive wildtype PABPN1 | gene therapies | EMA | Clinipace GmbH | |
Trehalose | small molecules | EMA | FGK Representative Service 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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