RARE DISEASE
Facioscapulohumeral dystrophy
Facioscapulohumeral dystrophy
Facioscapulohumeral dystrophy
Synonyms: FSH dystrophy, FSHD, Facioscapulohumeral muscular dystrophy, Facioscapulohumeral myopathy, Landouzy-Dejerine dystrophy, Landouzy-Dejerine myopathy
Synonyms: FSH dystrophy, FSHD, Facioscapulohumeral muscular dystrophy, Facioscapulohumeral myopathy, Landouzy-Dejerine dystrophy, Landouzy-Dejerine myopathy
Synonyms: FSH dystrophy, FSHD, Facioscapulohumeral muscular dystrophy, Facioscapulohumeral myopathy, Landouzy-Dejerine dystrophy, Landouzy-Dejerine myopathy
Drug discovery
18
drugs
With orphan designations
Overview
Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant muscle disorder characterized by progressive weakness in facial, shoulder, and upper arm muscles, often spreading to other muscle groups. Caused by misexpression of the DUX4 gene due to genetic/epigenetic dysregulation, it typically manifests in adolescence or adulthood (rarely in infancy) with variable severity. Extramuscular features include hearing loss (≤30% in childhood cases), retinal vascular abnormalities, and chronic pain. Respiratory/cardiac involvement is rare but possible in severe cases [1][5][6][11].
Burden
Economic: Annual per-patient costs exceed $28,000 (U.S.) and €26,322 (EU), driven by home care, assistive devices, and lost productivity [4][9].
Morbidity: 20% require wheelchairs by age 50; chronic pain affects >75% of patients [1][16].
Quality of life: Median health utility scores (0.63) reflect significant impairment vs. general populations [9][16].
Therapies
Symptomatic management: Physical therapy, scapular fixation surgery, pain management, and low-intensity aerobic exercise [1][6][11].
Emerging therapies: DUX4-targeted approaches (e.g., losmapimod [p38 inhibitor], CRISPR, antisense oligonucleotides) [3][13][18].
Trials: Anti-inflammatory/antioxidant agents (e.g., FLAVOMEGA, β2-agonists) show modest functional improvements [8][10].
Categories: rare genetic diseases, rare neurological diseases
Research Papers
542 drug discovery papers about Facioscapulohumeral dystrophy, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
542 drug discovery papers about Facioscapulohumeral dystrophy, with 3 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-31 | Metformin enhances differentiation and function of skeletal muscle in models of Facioscapulohumeral Muscular Dystrophy (FSHD)
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent inherited muscular dystrophies, for which there are no disease-modifying therapies. Metabolic perturbation, mitochondrial dysfunction, and oxidative stress are key contributors to FSHD pathology. Here, the effects of the metabolic regulator and anti-diabetic drug Metformin on myogenesis and muscle function in human and murine models of FSHD were investigated. Metformin did not affect the proliferation rate of human control or patient-derived FSHD myoblasts but promoted their myogenic differentiation, increasing myotube formation and maturation. Metformin also enhanced the metabolic health and viability of myotubes. Mechanistic interrogation revealed reduced levels of mitochondrial reactive oxygen species and modified mitochondrial turnover. These cellular investigations were complemented with in vivo functional assessment in a murine model of FSHD, in which Metformin treated mice exhibited significantly improved muscle strength. Collectively, these findings identify metabolic regulation as a therapeutically tractable feature of FSHD and demonstrate that Metformin improves muscle function in multiple models of FSHD via reduction of oxidative stress and augmentation of cellular metabolic fitness. These results provide insight into the therapeutic actions of Metformin and pre-clinical data to support its testing for repurposing in FSHD.
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.
2026-07-09 | Epigenetic editing approaches maturity: AI-driven precision design, delivery innovation, and the road to clinical translation.
Epigenetic editing achieves durable gene silencing through targeted modification of chromatin and DNA methylation states without altering the genomic sequence-modifications that remain fundamentally reversible compared with genome editing. Long constrained by transient efficacy, insufficient precision, and delivery bottlenecks, the field reached a critical inflection point in 2024-2025, measurable through three quantifiable criteria: (1) mechanistic durability-silencing maintained across ≥ 450 cell divisions in vitro and ≥ 12 months in vivo without continued editor expression; (2) delivery competence-tissue-selective transduction at > 50% efficiency in liver, muscle, and whole brain via engineered lipid nanoparticle and AAV platforms; and (3) clinical validation-advancement of multiple first-in-human trials. The inaugural trial in epigenetic editing was OTX-2002 (targeting MYC-driven malignancies, MYCHELANGELO study), initiated in October 2022, followed by TUNE-401 for chronic hepatitis B (Phase Ib, November 2024) and EPI-321 for facioscapulohumeral muscular dystrophy (Phase I/II, first patient dosed August 2025). Artificial intelligence contributes at distinct levels: deep learning platforms have directly accelerated clinical-stage LNP formulation screening and AAV capsid prediction; AlphaFold3 has optimized protein-DNA interaction validation without yet entering clinical programs; and the 2025 de novo design of DNA-binding proteins smaller than 65 amino acids represents a proof-of-concept breakthrough with zero clinical precedent. This review comprehensively analyzes epigenetic editing's technological maturation, provides a tiered assessment of AI's realized and anticipated contributions, critically evaluates the emerging clinical landscape, and identifies decisive unresolved challenges-including long-term stability in non-dividing cells, the lack of monitoring systems and intervention protocols needed to implement reversibility in clinical practice, and manufacturing access barriers. We argue that epigenetic editing is progressively establishing itself as a distinctive therapeutic modality characterized by durable efficacy and sequence-independent safety-reversibility as a theoretical safety mechanism has been validated preclinically, but the monitoring and intervention infrastructure required for its clinical implementation remains to be established. Long-term human validation remains the outstanding core question.
2026-06-19 | BAZ1A promotes expression of DUX4-fl and its lncRNA activator DBE-T in facioscapulohumeral muscular dystrophy
ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of a D4Z4 macrosatellite array, leading to pathogenic misexpression of DUX4 in skeletal muscle. Therapeutic development of small molecule drugs for FSHD has been hampered by screens that yield key myogenic regulators as candidates and a lack of mechanistic knowledge regarding their effects on DUX4 . To uncover more specific targets, we performed a candidate-based screen which identified several epigenetic facilitators of DUX4 expression in primary FSHD myocytes, including the chromatin remodeling factor BAZ1A. Here, we used a compound that we recently identified as a BAZ1A inhibitor and potent DUX4 suppressor to interrogate the role of BAZ1A at the FSHD locus. Our data suggest a model in which BAZ1A binds to D4Z4 in FSHD muscle, changing the chromatin landscape of the array. BAZ1A binding leads to reduced occupancy of the HP1α repressor, increased occupancy of the p300 coactivator, and increased H3K27 acetylation, promoting transcription of both DUX4 and the long non-coding RNA DBE-T from the disease locus. DBE-T, in turn, recruits the histone methyltransferase ASH1L, which establishes H3K36 methylation in cis, further promoting DUX4 transcription. BAZ1A inhibition disrupts this powerful feed-forward loop, supporting the development of more metabolically stable inhibitors. GRAPHICAL ABSTRACT
2026-05-25 | Elevated labile iron contributes to membrane repair deficits in facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by expression of the transcription factor DUX4, which is associated with plasma membrane (PM) repair deficits. Here, we show that PM injury triggers a mild but significant increase in DUX4 mRNA expression in FSHD myoblasts. These cells demonstrate the dysregulation of genes critical for PM repair, which are sensitive and specific for FSHD muscle tissue, and include regulators of ferroptosis. FSHD myoblasts also present with elevated labile ferrous iron and lipid peroxidation-hallmarks of ferroptotic stress. In FSHD muscle biopsies, the expression of ferroptosis biomarkers is elevated, predictive of inflammation. and positively correlated with fatty infiltration. Increasing labile iron and lipid peroxidation worsen PM repair in FSHD myoblasts, while treatment with the iron chelator 2,2'-Bipyridyl and ferroptosis inhibitor ferrostatin-1 improves repair. These data are the first to identify signs of ferroptotic stress in human FSHD myoblasts and demonstrate the potential benefit of targeting ferroptosis in FSHD.
cell therapies
2024-11-18 | Three-dimensional tissue engineered skeletal muscle modelling facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a three-dimensional tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients. 3D-TESMs derived from genetically affected MPs recapitulate pathological features including DUX4 and DUX4 target gene expression, smaller myofiber diameters, and reduced absolute forces upon electrical stimulation. RNA sequencing data illustrates increased expression of DUX4 target genes in 3D-TESMs compared to two-dimensional (2D) myotubes, and cellular differentiation was improved by 3D culture conditions. Treatment of 3D-TESMs with three different small molecules identified in drug development screens in 2D muscle cultures showed no improvements, and sometimes even declines, in contractile force and sarcomere organization. These results suggest that these compounds either have a detrimental effect on the formation of 3D-TESMs, an effect that might have been overlooked or was challenging to detect in 2D cultures and in vivo models, and/or that further development of the 3D-TESM model is needed. In conclusion, we have developed a 3D skeletal muscle model for FSHD that can be employed for preclinical research focusing on DUX4 expression and downstream pathways of FSHD in relation to contractile properties. In the future, we expect that this model can also be used for preclinical drug screening.
2024-05-31 | Scapulothoracic tenodesis using hamstring tendon graft for treatment of problematic scapula winging: A new surgical technique.
Winging of the scapula occurs due to dysfunction of its stabilising muscles, most commonly serratus anterior and/or trapezius, for example in facioscapulohumeral muscular dystrophy. Resultant loss of scapular control and abnormal kinematics can decrease shoulder function due to glenohumeral joint instability, loss of range of motion and pain. Previously described treatment for cases resistant to physiotherapy includes scapulothoracic arthrodesis which involves risk of non-union and metalwork failure, as well as reduced respiratory function due to immobilisation of a segment of the adjacent chest wall. We present a novel surgical approach to the management of problematic scapular winging by using hamstring graft to achieve a scapulothoracic tenodesis. We believe this technique provides an adequately stable scapula for improved shoulder movement and function, a sufficiently mobile chest wall for improved lung function and avoidance of complications specifically associated with arthrodesis.
2023-12-29 | Metabolic Changes during In Vivo Maturation of PSC-Derived Skeletal Myogenic Progenitors
In vitro-generated pluripotent stem cell (PSC)-derived Pax3-induced (iPax3) myogenic progenitors display an embryonic transcriptional signature, but upon engraftment, the profile of re-isolated iPax3 donor-derived satellite cells changes toward similarity with postnatal satellite cells, suggesting that engrafted PSC-derived myogenic cells remodel their transcriptional signature upon interaction within the adult muscle environment. Here, we show that engrafted myogenic progenitors also remodel their metabolic state. Assessment of oxygen consumption revealed that exposure to the adult muscle environment promotes overt changes in mitochondrial bioenergetics, as shown by the substantial suppression of energy requirements in re-isolated iPax3 donor-derived satellite cells compared to their in vitro-generated progenitors. Mass spectrometry-based metabolomic profiling further confirmed the relationship of engrafted iPax3 donor-derived cells to adult satellite cells. The fact that in vitro-generated myogenic progenitors remodel their bioenergetic signature upon in vivo exposure to the adult muscle environment may have important implications for therapeutic applications.
2022-09-16 | Non-myogenic mesenchymal cells contribute to muscle degeneration in facioscapulohumeral muscular dystrophy patients
Abstract Muscle-resident non-myogenic mesenchymal cells play key roles that drive successful tissue regeneration within the skeletal muscle stem cell niche. These cells have recently emerged as remarkable therapeutic targets for neuromuscular disorders, although to date they have been poorly investigated in facioscapulohumeral muscular dystrophy (FSHD). In this study, we characterised the non-myogenic mesenchymal stromal cell population in FSHD patients’ muscles with signs of disease activity, identified by muscle magnetic resonance imaging (MRI), and compared them with those obtained from apparently normal muscles of FSHD patients and from muscles of healthy, age-matched controls. Our results showed that patient-derived cells displayed a distinctive expression pattern of mesenchymal markers, along with an impaired capacity to differentiate towards mature adipocytes in vitro, compared with control cells. We also demonstrated a significant expansion of non-myogenic mesenchymal cells (identified as CD201- or PDGFRA-expressing cells) in FSHD muscles with signs of disease activity, which correlated with the extent of intramuscular fibrosis. In addition, the accumulation of non-myogenic mesenchymal cells was higher in FSHD muscles that deteriorate more rapidly. Our results prompt a direct association between an accumulation, as well as an altered differentiation, of non-myogenic mesenchymal cells with muscle degeneration in FSHD patients. Elucidating the mechanisms and cellular interactions that are altered in the affected muscles of FSHD patients could be instrumental to clarify disease pathogenesis and identifying reliable novel therapeutic targets.
2022-09-02 | Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. To investigate the potential for cell transplantation in FSHD, we have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. We find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft in muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis and importantly, engrafted muscles showed improved contractile specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacement of diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD, and highlight the potential for the clinical benefit of such a cell therapy approach.
oligonucleotides
2026-05-02 | Spatiotemporal DUX4 toxicity in FSHD: from epigenetic derepression to biomarker-driven targeted therapies.
Facioscapulohumeral muscular dystrophy (FSHD) is a gain-of-function genetic disorder caused by the loss of repressive epigenetic marks at the D4Z4 macrosatellite repeat array on chromosome 4q35. This epigenetic relaxation, when combined with a permissive 4q distal haplotype, defines the FSHD-permissive allele. Its transcription leads to the aberrant expression in skeletal muscle of the double homeobox transcription factor DUX4 (a gene normally confined to the earliest stages of embryogenesis), disrupting muscle homeostasis and triggering progressive degeneration. Over the past decade, extensive genetic and mechanistic studies have transformed the FSHD landscape. Despite the different genetic causes and the mosaic, temporally sporadic, spatially restricted nature of FSHD, a unified genetic model has emerged. Although the exact role of DUX4 in disease pathogenesis remains to be fully deciphered, a substantial body of evidence implicates it as the central driver of pathology. It is therefore an appealing therapeutic target, and several clinical trials are now underway to determine if suppressing its expression or activity is therapeutic. One of the current challenges in assessing these therapies is the identification of biomarkers capable of capturing disease activity, severity, and target engagement. This is especially challenging with a disease, like FSHD, that progresses slowly and heterogeneously. Progress in identifying biomarkers for potential clinical use marks a turning point for FSHD studies that can pave the way for therapies targeting the root cause of the disease. Here, we integrate what is known about the genetic and epigenetic mechanisms of DUX4 derepression with emerging evidence for spatiotemporal DUX4 toxicity in muscle. We argue that the mosaic expression of DUX4 has direct consequences for the design of biomarkers, the selection of biopsy muscles and sampling sites, and the appropriate endpoints in clinical trials. Finally, we outline a pragmatic approach to align DUX4-targeted and downstream therapies with biomarker strategies that are realistic for FSHD trial design.
2026-04-17 | Development of a DUX4-targeting antibody oligonucleotide conjugate as a therapy for FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease in which genetic mutations activate DUX4 expression in skeletal muscle. Currently, there are no approved therapies for FSHD. We developed Delpacibart braxlosiran (del-brax, also known as AOC 1020), an antibody oligonucleotide conjugate (AOC), for the treatment of FSHD that is designed to specifically target and reduce DUX4 mRNA in skeletal muscle. AOC 1020 is composed of DUX4 mRNA-targeting small interfering RNA (siRNA), siDUX4.6, conjugated to a human transferrin receptor 1 (TfR1)-targeting monoclonal antibody to facilitate productive siRNA delivery to muscle. We demonstrate that siDUX4.6 reduces DUX4-regulated gene expression in FSHD patient-derived myotubes in vitro and in skeletal muscle of the ACTA1-MCM; FLExDUX4 FSHD mouse model in vivo. Single systemic intravenous treatment was sufficient to prevent DUX4-induced muscle weakness and fibrosis in this FSHD mouse model and reduce DUX4-regulated genes by ∼75% 8 weeks post-dose. The pharmacokinetic profiles of AOCs with siDUX4.6 were comparable in murine and non-human primate muscle. These data demonstrate the potential of AOC 1020 to treat the underlying cause of FSHD by suppressing DUX4 expression in muscles of patients with FSHD. The safety and efficacy of AOC 1020 is currently being investigated in clinical trials.
2026-03-15 | Phase separation of DUX family proteins drives totipotent-like state via 3D genome reorganization and retrotransposon activation.
The acquisition of totipotency requires transcriptional activation of endogenous retroviruses (MERVL/HERVL) and zygotic genome activation (ZGA) related genes, yet the molecular mechanisms linking chromatin architecture to this process remain elusive. Here, we demonstrate that mouse Dux and human DUX4, double homeobox transcription factors essential for totipotency, form liquid-liquid phase-separated (LLPS) condensates through conserved arginine residues within intrinsically disordered regions (IDRs) in the Homeobox domain. These condensates recruit CBP/p300 and CTCF to establish super-enhancers (SEs) at MERVL/MT2 loci, enabling H3K27ac deposition and chromatin accessibility. Hi-C analysis revealed that DUX-driven phase separation facilitates 3D genome reorganization, including de novo formation of enhancer-promoter loops and TAD boundary shifts. Disruption of LLPS (DUXR70A) abolished SE assembly, transcriptional activation, and embryonic chimerism. Strikingly, human DUX4 required phase separation for both myotoxic gene activation and cytotoxicity in facioscapulohumeral muscular dystrophy (FSHD) models. Our study establishes a paradigm wherein phase separation integrates transcriptional control with 3D genome remodeling to license totipotency, with direct implications for developmental biology and disease therapy.
2026-01-15 | DUX4 reduction and muscle function improvement by subcutaneous delivery of gapmer antisense oligonucleotides.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of double homeodomain protein 4 (DUX4). The disease has no effective treatment. Previously we demonstrated effective DUX4 knockdown in vitro and in vivo using 2'-O-methoxyethyl (2'MOE) and locked nucleic acid (LNA) gapmer antisense oligonucleotides delivered via intramuscular injections. This study aimed to evaluate in vivo efficacy of the gapmers via systemic delivery using mouse models expressing DUX4 at different levels. First, we injected the gapmers subcutaneously to FLExDUX4 mice at 20 mg/kg twice a week for 10 weeks. Results showed significant reduction in DUX4 mRNA and improved muscle function, assessed by grip strength. Muscle fibrosis and circulating TGFβ1 levels were significantly reduced, approaching baseline level. A dose-dependent DUX4 reduction was observed in 2'MOE gapmer treated. In the ACTA1-MCM;FLExDUX4 model, where DUX4 expression was induced by tamoxifen (5 mg/kg), treatment with 2'MOE gapmers effectively reduced DUX4, improved muscle function, and decreased inflammation. These findings highlight the therapeutic potential of gapmer-based DUX4 reduction, leading to phenotypic improvement and restoration of muscle function in FSHD mouse models.
2025-08-07 | CEBPβ regulates myoblast proliferation and myogenic differentiation during human myogenesis and rescues defective differentiation in FSHD
Abstract CCAAT enhancer binding protein β (CEBPB) is a member of the bZIP transcription factor family and is expressed in many cell types. Whilst CEBPB has been shown to regulate the function of murine satellite cells, the resident skeletal muscle stem cell, however little is known of its role in human myogenesis and muscle disease. We report that CEBPB is expressed in proliferating human myoblasts but swiftly down-regulated upon myogenic differentiation. Interestingly, either over-expression or knock-down of CEBPB inhibit the proliferation rate of human myoblasts. Down-regulation of CEBPB upon myogenic differentiation is then necessary for subsequent myogenic differentiation and fusion into multinucleated myotubes. In the muscle disease context, CEBPB protein levels are increased in myoblasts derived from facioscapulohumeral muscular dystrophy (FSHD) patients. Knock-down of CEBPB in FSHD myoblasts improves myogenic differentiation. In summary, we show that CEBPB is a regulator of human myogenesis and altered CEBPB expression may contribute to defective myogenesis in FSHD.
gene therapies
2026-07-29 | Targeted DUX4 base editing improves muscle function in an iPSC-derived model of childhood-onset FSHD
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common dominant muscular dystrophies and remains without an approved disease modifying therapy. Caused by the aberrant expression of the cytotoxic gene DUX4, FSHD is typically diagnosed in adulthood, however clinical onset in children (<18 years of age) is often associated with a more severe and rapid disease. While clinical trials are underway, a lack of human-specific pre-clinical models limit effective testing of potential therapies, particularly in children. To fill this gap, we describe here the development of induced pluripotent stem cell-derived 2-and 3-dimensional skeletal muscle models of children with clinically defined mild, moderate, and severe FSHD. These iPSC-derived muscle models replicate key features of FSHD, including aberrant DUX4 mRNA expression, muscle atrophy, and weakness, which correlate with the individuals’ specific disease severity. Next, we assessed the efficacy of adenine base editing (ABE) as a potential gene therapy approach to treat FSHD. DUX4 -targeted ABE reduced DUX4 mRNA expression, improved muscle area and force generation in the most severe individual. Together this work supports the use of iPSC-derived skeletal muscle models as a less invasive method to study childhood-onset FSHD and establishes targeted DUX4 gene editing therapies as a potential treatment approach.
2026-07-02 | MYH2 as a Potential Modifier of Clinical Severity in Facioscapulohumeral Muscular Dystrophy.
Facioscapulohumeral muscular dystrophy(FSHD) is a genetic and heterogeneous neuromuscular disorder primarily driven by DUX4 derepression. The marked clinical variability observed among affected individuals suggests the presence of additional genetic modifiers, however underlying factors remain largely unclear. Investigating coincidental hereditary conditions within families may provide critical insights into such modifying mechanisms. We investigated a multigenerational family exhibiting the co-occurrence of FSHD and hereditary macrothrombocytopenia. Detailed neurological and hematological evaluations were performed across family members. Trio whole-exome sequencing(WES) was performed in selected individuals, followed by DNA sequencing and segregation analysis of identified genes. In silico structural analyses were performed for candidate variants. Candidate variants were additionally screened in an independent cohort with next generation sequencing. Clinical severity was assessed using the Clinical severity score(CSS), FSHD clinical score, and age-corrected CSS(ACSS). Trio-WES analysis identified a pathogenic frameshift mutation(c.1848delT) in GP1BA gene, responsible for macrothrombocytopenia. Among candidate variants located near GP1BA, a missense variant in MYH2(c.5045G > A) was prioritized due to its known association with myopathy and its involvement in DUX4-related pathways. Segregation analysis revealed that GP1BA mutations were present in five of nine FSHD-affected individuals, four of whom also harboured the MYH2 variant. Neither mutation was detected in unaffected family members. Individuals carrying the MYH2 variant consistently exhibited higher ACSS values compared to family members who did not carry the variant. Screening of MYH2 c.5045G > A (p.Arg1682His) and GP1BA c.1848delT variants in an independent cohort of 30 FSHD1 patients revealed no variant carriers, with all individuals exhibiting a wild-type genotype. Network analysis focusing on the interaction landscape between the FSHD key protein DUX4 and MYH2, using the Integrated Interactions Database(IID), revealed ACTN1 as a connecting node linking these pathways. Our findings suggest that rare MYH2 variants may act as a genetic modifier influencing the clinical severity in FSHD, which has not been previously reported. This study highlights the value of investigating co-occurring hereditary conditions to uncover novel molecular contributors to disease heterogeneity in FSHD. The potential role of MYH2 and its rare variants as genetic modifiers should be further validated in larger cohorts and functional studies.
2026-05-15 | Development of in vitro potency assays for AAV-based gene silencing therapies targeting FSHD and CMT1A.
Adeno-associated viral (AAV) vectors are a cornerstone system for delivering gene therapies for several diseases, including two under development in our lab: Charcot-Marie-Tooth disease type 1A (CMT1A) and facioscapulohumeral muscular dystrophy (FSHD). Although most AAV therapies today involve gene replacement for recessive disorders, CMT1A and FSHD are dominant diseases that would benefit from disease gene silencing, and we have generated extensive pre-clinical safety and efficacy data to support translating gene therapies for both diseases. Here, in anticipation of clinical trials and, optimistically, post-approval, we describe our approach to develop a robust potency assay to assess product strength and stability. To do this, we modified HEK293T cells to increase permissibility to AAV transduction and produce a quantifiable, treatment-responsive readout. Specifically, we created stable cell lines containing (1) the AAV receptor (AAVR) to improve AAV transduction and (2) a Renilla luciferase (rLuc) open reading frame with disease gene sequences in the 3' UTR, to enable disease gene knockdown quantification by luciferase assay. Our study provides a straightforward framework for potency assay development supporting AAV-mediated and non-viral gene silencing programs.
2025-11-01 | Response to: Disentangling Facioscapulohumeral Muscular Dystrophy Disability From Age and Comorbidities: A Call for Refined Stratification
Contains fulltext : 327761.pdf (Publisher’s version ) (Open Access)
2025-09-02 | All-in-one vectors for epigenetic CRISPR inhibition of DUX4-fl in facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Previously, we showed that CRISPR inhibition (CRISPRi) using several epigenetic regulators successfully targets and represses DUX4 in FSHD myocytes with no adverse effects on the muscle transcriptome. However, for translatability, adeno-associated virus (AAV)-mediated gene therapies must include all components within a single vector that expresses at therapeutic levels in all target tissues. Thus, we have re-engineered our CRISPRi platform to an all-in-one (AIO) single-vector system. Key modifications were as follows: (1) optimizing our regulatory cassette for high activity in all skeletal muscles while maintaining low or no activity in FSHD-unaffected tissues and (2) minimizing epigenetic regulators to their essential functional repressor domains, together creating enough space to include a single guide RNA (sgRNA) expression cassette within the AAV packaging limit. Targeting these AIO cargos to DUX4 suppressed pathogenic gene expression in FSHD1 and FSHD2 myocytes. Importantly, AAV-mediated delivery of our best AIO cargo also repressed DUX4 in an FSHD xenograft mouse model. These therapeutic cassettes represent a clinically relevant CRISPRi platform for gene therapy of FSHD and a useful proof-of-concept platform for other skeletal muscle gene therapies.
other
2026-08-05 | In vitro and in silico characterization of competitive inhibition and repression of DUX4 target gene activation as a therapeutic approach for facioscapulohumeral muscular dystrophy (FSHD)
ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is a rare neuromuscular disease caused by aberrant re-expression of the embryonic transcription factor DUX4 in skeletal muscle, which activates a toxic transcriptional program that drives progressive muscle wasting. No approved disease-modifying therapies currently exist. Prior work in mammalian and zebrafish models has shown that a truncated form of DUX4 retaining only its DNA-binding domain (DBD) lacks transactivation capacity and can suppress DUX4-FL-driven pathology; separately, dCas9/KRAB-based epigenetic repressors have demonstrated efficacy in silencing DUX4 expression, though CRISPR-based strategies face challenges from the repetitive nature of the D4Z4 locus, the immunogenicity associated with bacterial Cas proteins, and the payload limitations of gene delivery vehicles. Building on these findings, we corroborate that the DUX4 DBD, comprising both homeodomains, acts as a non-toxic competitive inhibitor of full-length DUX4 (DUX4-FL) at its genomic target sites, and extend this strategy by fusing the DBD to a human KRAB(ZNF10) domain, converting DUX4 from a transcriptional activator into a fully humanized epigenetic silencer of its own targets. Using a fluorescent DUX4-responsive reporter, we show that DBD alone produces dose-dependent repression of DUX4-FL transcriptional activity in HEK293T cells (200-fold at the highest inducible dose tested), while a constitutively expressed DBD-KRAB fusion produces significantly greater repression than DBD alone (949-fold versus 17-fold at a 25x molar ratio), with a similar trend observed in C2C12 myoblasts (47-fold versus 3.3-fold knockdown). To contextualize these findings and explore dosing considerations, we developed three complementary computational models – a transcription factor competitive binding model, a myotube diffusion model, and an ordinary differential equation (ODE) compartmental model – that illustrate how DBD concentration, intracellular diffusion, and population-level cell state transitions may relate to therapeutic efficacy. Together, these results corroborate and extend existing approaches into a single, fully humanized construct that may help circumvent the immunogenicity and delivery limitations of Cas-based systems.
2024-02-04 | SMCHD1 activates the expression of genes required for the expansion of human myoblasts
ABSTRACT SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4 . Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression. Chromatin modifier SMCHD1 regulates the proliferation of human myoblasts SMCHD1 binds to enhancers of cell cycle regulatory genes to activate their expression Lap2 is an SMCHD1 direct target gene that regulates the expansion of human myoblasts.
2022-07-14 | Multimodal Imaging Findings in Retinopathy Associated with Facioscapulohumeral Muscular Dystrophy before and after Treatment with Intravitreal Aflibercept and Laser Photocoagulation
A 52-year-old man with a history of facioscapulohumeral dystrophy (FSHD) and hypertension presented with decreased vision in his left eye (OS) of several weeks' duration. The best-corrected visual acuity was 1.0 in both eyes (OU), with fundus soft exudates in the right eye (OD) and exudative maculopathy OS. Optical coherence tomography (OCT) showed macular edema and hard exudates OS, and OCT angiography (OCTA) showed nonperfusion areas and arterial tortuosity OU and a capillary aneurysm OS. After photocoagulation of the nonperfusion areas OU and intravitreal injection of aflibercept OS, the macular edema OS decreased and subjective symptoms improved. However, the nonperfusion area OS was enlarged on OCTA. We report the OCTA findings before and after antivascular endothelial growth factor treatment in a patient with FSHD.
2022-04-27 | Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis.
Inappropriate expression of DUX4, a transcription factor that induces cell death at high levels of expression and impairs myoblast differentiation at low levels of expression, leads to the development of facioscapulohumeral muscular dystrophy (FSHD), however, the pathological mechanisms downstream of DUX4 responsible for muscle loss are poorly defined. We performed a screen of 1972 miR inhibitors for their ability to interfere with DUX4-induced cell death of human immortalized myoblasts. The most potent hit identified by the screen, miR-3202, is known to target the antiapoptotic protein FAIM2. Inhibition of miR-3202 led to the upregulation of FAIM2, and remarkably, expression of DUX4 led to reduced cellular levels of FAIM2. We show that the E3 ubiquitin ligase and DUX4 target gene, TRIM21, is responsible for FAIM2 degradation downstream of DUX4. Human myoblasts overexpressing FAIM2 showed increased resistance to DUX4-induced cell death, whereas in wild-type cells FAIM2 knockdown resulted in increased apoptosis and failure to differentiate into myotubes. The necessity of FAIM2 for myogenic differentiation of WT cells led us to test the effect of FAIM2 overexpression on the impairment of myogenesis by DUX4. Strikingly, FAIM2 overexpression rescued the myogenic differentiation defect caused by low-level expression of DUX4. These data implicate FAIM2 levels, modulated by DUX4 through TRIM21, as an important factor mediating the pathogenicity of DUX4, both in terms of cell viability and myogenic differentiation, and thereby open a new avenue of investigation towards drug targets in FSHD.
2022-04-16 | Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD.Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated.Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions.Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
small molecules
2026-07-31 | Metformin enhances differentiation and function of skeletal muscle in models of Facioscapulohumeral Muscular Dystrophy (FSHD)
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent inherited muscular dystrophies, for which there are no disease-modifying therapies. Metabolic perturbation, mitochondrial dysfunction, and oxidative stress are key contributors to FSHD pathology. Here, the effects of the metabolic regulator and anti-diabetic drug Metformin on myogenesis and muscle function in human and murine models of FSHD were investigated. Metformin did not affect the proliferation rate of human control or patient-derived FSHD myoblasts but promoted their myogenic differentiation, increasing myotube formation and maturation. Metformin also enhanced the metabolic health and viability of myotubes. Mechanistic interrogation revealed reduced levels of mitochondrial reactive oxygen species and modified mitochondrial turnover. These cellular investigations were complemented with in vivo functional assessment in a murine model of FSHD, in which Metformin treated mice exhibited significantly improved muscle strength. Collectively, these findings identify metabolic regulation as a therapeutically tractable feature of FSHD and demonstrate that Metformin improves muscle function in multiple models of FSHD via reduction of oxidative stress and augmentation of cellular metabolic fitness. These results provide insight into the therapeutic actions of Metformin and pre-clinical data to support its testing for repurposing in FSHD.
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.
2026-07-09 | Epigenetic editing approaches maturity: AI-driven precision design, delivery innovation, and the road to clinical translation.
Epigenetic editing achieves durable gene silencing through targeted modification of chromatin and DNA methylation states without altering the genomic sequence-modifications that remain fundamentally reversible compared with genome editing. Long constrained by transient efficacy, insufficient precision, and delivery bottlenecks, the field reached a critical inflection point in 2024-2025, measurable through three quantifiable criteria: (1) mechanistic durability-silencing maintained across ≥ 450 cell divisions in vitro and ≥ 12 months in vivo without continued editor expression; (2) delivery competence-tissue-selective transduction at > 50% efficiency in liver, muscle, and whole brain via engineered lipid nanoparticle and AAV platforms; and (3) clinical validation-advancement of multiple first-in-human trials. The inaugural trial in epigenetic editing was OTX-2002 (targeting MYC-driven malignancies, MYCHELANGELO study), initiated in October 2022, followed by TUNE-401 for chronic hepatitis B (Phase Ib, November 2024) and EPI-321 for facioscapulohumeral muscular dystrophy (Phase I/II, first patient dosed August 2025). Artificial intelligence contributes at distinct levels: deep learning platforms have directly accelerated clinical-stage LNP formulation screening and AAV capsid prediction; AlphaFold3 has optimized protein-DNA interaction validation without yet entering clinical programs; and the 2025 de novo design of DNA-binding proteins smaller than 65 amino acids represents a proof-of-concept breakthrough with zero clinical precedent. This review comprehensively analyzes epigenetic editing's technological maturation, provides a tiered assessment of AI's realized and anticipated contributions, critically evaluates the emerging clinical landscape, and identifies decisive unresolved challenges-including long-term stability in non-dividing cells, the lack of monitoring systems and intervention protocols needed to implement reversibility in clinical practice, and manufacturing access barriers. We argue that epigenetic editing is progressively establishing itself as a distinctive therapeutic modality characterized by durable efficacy and sequence-independent safety-reversibility as a theoretical safety mechanism has been validated preclinically, but the monitoring and intervention infrastructure required for its clinical implementation remains to be established. Long-term human validation remains the outstanding core question.
2026-06-19 | BAZ1A promotes expression of DUX4-fl and its lncRNA activator DBE-T in facioscapulohumeral muscular dystrophy
ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of a D4Z4 macrosatellite array, leading to pathogenic misexpression of DUX4 in skeletal muscle. Therapeutic development of small molecule drugs for FSHD has been hampered by screens that yield key myogenic regulators as candidates and a lack of mechanistic knowledge regarding their effects on DUX4 . To uncover more specific targets, we performed a candidate-based screen which identified several epigenetic facilitators of DUX4 expression in primary FSHD myocytes, including the chromatin remodeling factor BAZ1A. Here, we used a compound that we recently identified as a BAZ1A inhibitor and potent DUX4 suppressor to interrogate the role of BAZ1A at the FSHD locus. Our data suggest a model in which BAZ1A binds to D4Z4 in FSHD muscle, changing the chromatin landscape of the array. BAZ1A binding leads to reduced occupancy of the HP1α repressor, increased occupancy of the p300 coactivator, and increased H3K27 acetylation, promoting transcription of both DUX4 and the long non-coding RNA DBE-T from the disease locus. DBE-T, in turn, recruits the histone methyltransferase ASH1L, which establishes H3K36 methylation in cis, further promoting DUX4 transcription. BAZ1A inhibition disrupts this powerful feed-forward loop, supporting the development of more metabolically stable inhibitors. GRAPHICAL ABSTRACT
2026-05-25 | Elevated labile iron contributes to membrane repair deficits in facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by expression of the transcription factor DUX4, which is associated with plasma membrane (PM) repair deficits. Here, we show that PM injury triggers a mild but significant increase in DUX4 mRNA expression in FSHD myoblasts. These cells demonstrate the dysregulation of genes critical for PM repair, which are sensitive and specific for FSHD muscle tissue, and include regulators of ferroptosis. FSHD myoblasts also present with elevated labile ferrous iron and lipid peroxidation-hallmarks of ferroptotic stress. In FSHD muscle biopsies, the expression of ferroptosis biomarkers is elevated, predictive of inflammation. and positively correlated with fatty infiltration. Increasing labile iron and lipid peroxidation worsen PM repair in FSHD myoblasts, while treatment with the iron chelator 2,2'-Bipyridyl and ferroptosis inhibitor ferrostatin-1 improves repair. These data are the first to identify signs of ferroptotic stress in human FSHD myoblasts and demonstrate the potential benefit of targeting ferroptosis in FSHD.
cell therapies
2024-11-18 | Three-dimensional tissue engineered skeletal muscle modelling facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by sporadic misexpression of the transcription factor double homeobox 4 (DUX4) in skeletal muscles. So far, monolayer cultures and animal models have been used to study the FSHD disease mechanism and for FSHD therapy development, but these models do not fully recapitulate the disease and there is a lack of knowledge on how DUX4 misexpression leads to skeletal muscle dysfunction. To overcome these barriers, we have developed a three-dimensional tissue engineered skeletal muscle (3D-TESM) model by generating genetically matched myogenic progenitors (MPs) from human induced pluripotent stem cells of three mosaic FSHD patients. 3D-TESMs derived from genetically affected MPs recapitulate pathological features including DUX4 and DUX4 target gene expression, smaller myofiber diameters, and reduced absolute forces upon electrical stimulation. RNA sequencing data illustrates increased expression of DUX4 target genes in 3D-TESMs compared to two-dimensional (2D) myotubes, and cellular differentiation was improved by 3D culture conditions. Treatment of 3D-TESMs with three different small molecules identified in drug development screens in 2D muscle cultures showed no improvements, and sometimes even declines, in contractile force and sarcomere organization. These results suggest that these compounds either have a detrimental effect on the formation of 3D-TESMs, an effect that might have been overlooked or was challenging to detect in 2D cultures and in vivo models, and/or that further development of the 3D-TESM model is needed. In conclusion, we have developed a 3D skeletal muscle model for FSHD that can be employed for preclinical research focusing on DUX4 expression and downstream pathways of FSHD in relation to contractile properties. In the future, we expect that this model can also be used for preclinical drug screening.
2024-05-31 | Scapulothoracic tenodesis using hamstring tendon graft for treatment of problematic scapula winging: A new surgical technique.
Winging of the scapula occurs due to dysfunction of its stabilising muscles, most commonly serratus anterior and/or trapezius, for example in facioscapulohumeral muscular dystrophy. Resultant loss of scapular control and abnormal kinematics can decrease shoulder function due to glenohumeral joint instability, loss of range of motion and pain. Previously described treatment for cases resistant to physiotherapy includes scapulothoracic arthrodesis which involves risk of non-union and metalwork failure, as well as reduced respiratory function due to immobilisation of a segment of the adjacent chest wall. We present a novel surgical approach to the management of problematic scapular winging by using hamstring graft to achieve a scapulothoracic tenodesis. We believe this technique provides an adequately stable scapula for improved shoulder movement and function, a sufficiently mobile chest wall for improved lung function and avoidance of complications specifically associated with arthrodesis.
2023-12-29 | Metabolic Changes during In Vivo Maturation of PSC-Derived Skeletal Myogenic Progenitors
In vitro-generated pluripotent stem cell (PSC)-derived Pax3-induced (iPax3) myogenic progenitors display an embryonic transcriptional signature, but upon engraftment, the profile of re-isolated iPax3 donor-derived satellite cells changes toward similarity with postnatal satellite cells, suggesting that engrafted PSC-derived myogenic cells remodel their transcriptional signature upon interaction within the adult muscle environment. Here, we show that engrafted myogenic progenitors also remodel their metabolic state. Assessment of oxygen consumption revealed that exposure to the adult muscle environment promotes overt changes in mitochondrial bioenergetics, as shown by the substantial suppression of energy requirements in re-isolated iPax3 donor-derived satellite cells compared to their in vitro-generated progenitors. Mass spectrometry-based metabolomic profiling further confirmed the relationship of engrafted iPax3 donor-derived cells to adult satellite cells. The fact that in vitro-generated myogenic progenitors remodel their bioenergetic signature upon in vivo exposure to the adult muscle environment may have important implications for therapeutic applications.
2022-09-16 | Non-myogenic mesenchymal cells contribute to muscle degeneration in facioscapulohumeral muscular dystrophy patients
Abstract Muscle-resident non-myogenic mesenchymal cells play key roles that drive successful tissue regeneration within the skeletal muscle stem cell niche. These cells have recently emerged as remarkable therapeutic targets for neuromuscular disorders, although to date they have been poorly investigated in facioscapulohumeral muscular dystrophy (FSHD). In this study, we characterised the non-myogenic mesenchymal stromal cell population in FSHD patients’ muscles with signs of disease activity, identified by muscle magnetic resonance imaging (MRI), and compared them with those obtained from apparently normal muscles of FSHD patients and from muscles of healthy, age-matched controls. Our results showed that patient-derived cells displayed a distinctive expression pattern of mesenchymal markers, along with an impaired capacity to differentiate towards mature adipocytes in vitro, compared with control cells. We also demonstrated a significant expansion of non-myogenic mesenchymal cells (identified as CD201- or PDGFRA-expressing cells) in FSHD muscles with signs of disease activity, which correlated with the extent of intramuscular fibrosis. In addition, the accumulation of non-myogenic mesenchymal cells was higher in FSHD muscles that deteriorate more rapidly. Our results prompt a direct association between an accumulation, as well as an altered differentiation, of non-myogenic mesenchymal cells with muscle degeneration in FSHD patients. Elucidating the mechanisms and cellular interactions that are altered in the affected muscles of FSHD patients could be instrumental to clarify disease pathogenesis and identifying reliable novel therapeutic targets.
2022-09-02 | Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. To investigate the potential for cell transplantation in FSHD, we have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. We find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft in muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis and importantly, engrafted muscles showed improved contractile specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacement of diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD, and highlight the potential for the clinical benefit of such a cell therapy approach.
oligonucleotides
2026-05-02 | Spatiotemporal DUX4 toxicity in FSHD: from epigenetic derepression to biomarker-driven targeted therapies.
Facioscapulohumeral muscular dystrophy (FSHD) is a gain-of-function genetic disorder caused by the loss of repressive epigenetic marks at the D4Z4 macrosatellite repeat array on chromosome 4q35. This epigenetic relaxation, when combined with a permissive 4q distal haplotype, defines the FSHD-permissive allele. Its transcription leads to the aberrant expression in skeletal muscle of the double homeobox transcription factor DUX4 (a gene normally confined to the earliest stages of embryogenesis), disrupting muscle homeostasis and triggering progressive degeneration. Over the past decade, extensive genetic and mechanistic studies have transformed the FSHD landscape. Despite the different genetic causes and the mosaic, temporally sporadic, spatially restricted nature of FSHD, a unified genetic model has emerged. Although the exact role of DUX4 in disease pathogenesis remains to be fully deciphered, a substantial body of evidence implicates it as the central driver of pathology. It is therefore an appealing therapeutic target, and several clinical trials are now underway to determine if suppressing its expression or activity is therapeutic. One of the current challenges in assessing these therapies is the identification of biomarkers capable of capturing disease activity, severity, and target engagement. This is especially challenging with a disease, like FSHD, that progresses slowly and heterogeneously. Progress in identifying biomarkers for potential clinical use marks a turning point for FSHD studies that can pave the way for therapies targeting the root cause of the disease. Here, we integrate what is known about the genetic and epigenetic mechanisms of DUX4 derepression with emerging evidence for spatiotemporal DUX4 toxicity in muscle. We argue that the mosaic expression of DUX4 has direct consequences for the design of biomarkers, the selection of biopsy muscles and sampling sites, and the appropriate endpoints in clinical trials. Finally, we outline a pragmatic approach to align DUX4-targeted and downstream therapies with biomarker strategies that are realistic for FSHD trial design.
2026-04-17 | Development of a DUX4-targeting antibody oligonucleotide conjugate as a therapy for FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscular disease in which genetic mutations activate DUX4 expression in skeletal muscle. Currently, there are no approved therapies for FSHD. We developed Delpacibart braxlosiran (del-brax, also known as AOC 1020), an antibody oligonucleotide conjugate (AOC), for the treatment of FSHD that is designed to specifically target and reduce DUX4 mRNA in skeletal muscle. AOC 1020 is composed of DUX4 mRNA-targeting small interfering RNA (siRNA), siDUX4.6, conjugated to a human transferrin receptor 1 (TfR1)-targeting monoclonal antibody to facilitate productive siRNA delivery to muscle. We demonstrate that siDUX4.6 reduces DUX4-regulated gene expression in FSHD patient-derived myotubes in vitro and in skeletal muscle of the ACTA1-MCM; FLExDUX4 FSHD mouse model in vivo. Single systemic intravenous treatment was sufficient to prevent DUX4-induced muscle weakness and fibrosis in this FSHD mouse model and reduce DUX4-regulated genes by ∼75% 8 weeks post-dose. The pharmacokinetic profiles of AOCs with siDUX4.6 were comparable in murine and non-human primate muscle. These data demonstrate the potential of AOC 1020 to treat the underlying cause of FSHD by suppressing DUX4 expression in muscles of patients with FSHD. The safety and efficacy of AOC 1020 is currently being investigated in clinical trials.
2026-03-15 | Phase separation of DUX family proteins drives totipotent-like state via 3D genome reorganization and retrotransposon activation.
The acquisition of totipotency requires transcriptional activation of endogenous retroviruses (MERVL/HERVL) and zygotic genome activation (ZGA) related genes, yet the molecular mechanisms linking chromatin architecture to this process remain elusive. Here, we demonstrate that mouse Dux and human DUX4, double homeobox transcription factors essential for totipotency, form liquid-liquid phase-separated (LLPS) condensates through conserved arginine residues within intrinsically disordered regions (IDRs) in the Homeobox domain. These condensates recruit CBP/p300 and CTCF to establish super-enhancers (SEs) at MERVL/MT2 loci, enabling H3K27ac deposition and chromatin accessibility. Hi-C analysis revealed that DUX-driven phase separation facilitates 3D genome reorganization, including de novo formation of enhancer-promoter loops and TAD boundary shifts. Disruption of LLPS (DUXR70A) abolished SE assembly, transcriptional activation, and embryonic chimerism. Strikingly, human DUX4 required phase separation for both myotoxic gene activation and cytotoxicity in facioscapulohumeral muscular dystrophy (FSHD) models. Our study establishes a paradigm wherein phase separation integrates transcriptional control with 3D genome remodeling to license totipotency, with direct implications for developmental biology and disease therapy.
2026-01-15 | DUX4 reduction and muscle function improvement by subcutaneous delivery of gapmer antisense oligonucleotides.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by aberrant expression of double homeodomain protein 4 (DUX4). The disease has no effective treatment. Previously we demonstrated effective DUX4 knockdown in vitro and in vivo using 2'-O-methoxyethyl (2'MOE) and locked nucleic acid (LNA) gapmer antisense oligonucleotides delivered via intramuscular injections. This study aimed to evaluate in vivo efficacy of the gapmers via systemic delivery using mouse models expressing DUX4 at different levels. First, we injected the gapmers subcutaneously to FLExDUX4 mice at 20 mg/kg twice a week for 10 weeks. Results showed significant reduction in DUX4 mRNA and improved muscle function, assessed by grip strength. Muscle fibrosis and circulating TGFβ1 levels were significantly reduced, approaching baseline level. A dose-dependent DUX4 reduction was observed in 2'MOE gapmer treated. In the ACTA1-MCM;FLExDUX4 model, where DUX4 expression was induced by tamoxifen (5 mg/kg), treatment with 2'MOE gapmers effectively reduced DUX4, improved muscle function, and decreased inflammation. These findings highlight the therapeutic potential of gapmer-based DUX4 reduction, leading to phenotypic improvement and restoration of muscle function in FSHD mouse models.
2025-08-07 | CEBPβ regulates myoblast proliferation and myogenic differentiation during human myogenesis and rescues defective differentiation in FSHD
Abstract CCAAT enhancer binding protein β (CEBPB) is a member of the bZIP transcription factor family and is expressed in many cell types. Whilst CEBPB has been shown to regulate the function of murine satellite cells, the resident skeletal muscle stem cell, however little is known of its role in human myogenesis and muscle disease. We report that CEBPB is expressed in proliferating human myoblasts but swiftly down-regulated upon myogenic differentiation. Interestingly, either over-expression or knock-down of CEBPB inhibit the proliferation rate of human myoblasts. Down-regulation of CEBPB upon myogenic differentiation is then necessary for subsequent myogenic differentiation and fusion into multinucleated myotubes. In the muscle disease context, CEBPB protein levels are increased in myoblasts derived from facioscapulohumeral muscular dystrophy (FSHD) patients. Knock-down of CEBPB in FSHD myoblasts improves myogenic differentiation. In summary, we show that CEBPB is a regulator of human myogenesis and altered CEBPB expression may contribute to defective myogenesis in FSHD.
gene therapies
2026-07-29 | Targeted DUX4 base editing improves muscle function in an iPSC-derived model of childhood-onset FSHD
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common dominant muscular dystrophies and remains without an approved disease modifying therapy. Caused by the aberrant expression of the cytotoxic gene DUX4, FSHD is typically diagnosed in adulthood, however clinical onset in children (<18 years of age) is often associated with a more severe and rapid disease. While clinical trials are underway, a lack of human-specific pre-clinical models limit effective testing of potential therapies, particularly in children. To fill this gap, we describe here the development of induced pluripotent stem cell-derived 2-and 3-dimensional skeletal muscle models of children with clinically defined mild, moderate, and severe FSHD. These iPSC-derived muscle models replicate key features of FSHD, including aberrant DUX4 mRNA expression, muscle atrophy, and weakness, which correlate with the individuals’ specific disease severity. Next, we assessed the efficacy of adenine base editing (ABE) as a potential gene therapy approach to treat FSHD. DUX4 -targeted ABE reduced DUX4 mRNA expression, improved muscle area and force generation in the most severe individual. Together this work supports the use of iPSC-derived skeletal muscle models as a less invasive method to study childhood-onset FSHD and establishes targeted DUX4 gene editing therapies as a potential treatment approach.
2026-07-02 | MYH2 as a Potential Modifier of Clinical Severity in Facioscapulohumeral Muscular Dystrophy.
Facioscapulohumeral muscular dystrophy(FSHD) is a genetic and heterogeneous neuromuscular disorder primarily driven by DUX4 derepression. The marked clinical variability observed among affected individuals suggests the presence of additional genetic modifiers, however underlying factors remain largely unclear. Investigating coincidental hereditary conditions within families may provide critical insights into such modifying mechanisms. We investigated a multigenerational family exhibiting the co-occurrence of FSHD and hereditary macrothrombocytopenia. Detailed neurological and hematological evaluations were performed across family members. Trio whole-exome sequencing(WES) was performed in selected individuals, followed by DNA sequencing and segregation analysis of identified genes. In silico structural analyses were performed for candidate variants. Candidate variants were additionally screened in an independent cohort with next generation sequencing. Clinical severity was assessed using the Clinical severity score(CSS), FSHD clinical score, and age-corrected CSS(ACSS). Trio-WES analysis identified a pathogenic frameshift mutation(c.1848delT) in GP1BA gene, responsible for macrothrombocytopenia. Among candidate variants located near GP1BA, a missense variant in MYH2(c.5045G > A) was prioritized due to its known association with myopathy and its involvement in DUX4-related pathways. Segregation analysis revealed that GP1BA mutations were present in five of nine FSHD-affected individuals, four of whom also harboured the MYH2 variant. Neither mutation was detected in unaffected family members. Individuals carrying the MYH2 variant consistently exhibited higher ACSS values compared to family members who did not carry the variant. Screening of MYH2 c.5045G > A (p.Arg1682His) and GP1BA c.1848delT variants in an independent cohort of 30 FSHD1 patients revealed no variant carriers, with all individuals exhibiting a wild-type genotype. Network analysis focusing on the interaction landscape between the FSHD key protein DUX4 and MYH2, using the Integrated Interactions Database(IID), revealed ACTN1 as a connecting node linking these pathways. Our findings suggest that rare MYH2 variants may act as a genetic modifier influencing the clinical severity in FSHD, which has not been previously reported. This study highlights the value of investigating co-occurring hereditary conditions to uncover novel molecular contributors to disease heterogeneity in FSHD. The potential role of MYH2 and its rare variants as genetic modifiers should be further validated in larger cohorts and functional studies.
2026-05-15 | Development of in vitro potency assays for AAV-based gene silencing therapies targeting FSHD and CMT1A.
Adeno-associated viral (AAV) vectors are a cornerstone system for delivering gene therapies for several diseases, including two under development in our lab: Charcot-Marie-Tooth disease type 1A (CMT1A) and facioscapulohumeral muscular dystrophy (FSHD). Although most AAV therapies today involve gene replacement for recessive disorders, CMT1A and FSHD are dominant diseases that would benefit from disease gene silencing, and we have generated extensive pre-clinical safety and efficacy data to support translating gene therapies for both diseases. Here, in anticipation of clinical trials and, optimistically, post-approval, we describe our approach to develop a robust potency assay to assess product strength and stability. To do this, we modified HEK293T cells to increase permissibility to AAV transduction and produce a quantifiable, treatment-responsive readout. Specifically, we created stable cell lines containing (1) the AAV receptor (AAVR) to improve AAV transduction and (2) a Renilla luciferase (rLuc) open reading frame with disease gene sequences in the 3' UTR, to enable disease gene knockdown quantification by luciferase assay. Our study provides a straightforward framework for potency assay development supporting AAV-mediated and non-viral gene silencing programs.
2025-11-01 | Response to: Disentangling Facioscapulohumeral Muscular Dystrophy Disability From Age and Comorbidities: A Call for Refined Stratification
Contains fulltext : 327761.pdf (Publisher’s version ) (Open Access)
2025-09-02 | All-in-one vectors for epigenetic CRISPR inhibition of DUX4-fl in facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is caused by incomplete epigenetic silencing of the disease locus, leading to pathogenic misexpression of DUX4 in skeletal muscle. Previously, we showed that CRISPR inhibition (CRISPRi) using several epigenetic regulators successfully targets and represses DUX4 in FSHD myocytes with no adverse effects on the muscle transcriptome. However, for translatability, adeno-associated virus (AAV)-mediated gene therapies must include all components within a single vector that expresses at therapeutic levels in all target tissues. Thus, we have re-engineered our CRISPRi platform to an all-in-one (AIO) single-vector system. Key modifications were as follows: (1) optimizing our regulatory cassette for high activity in all skeletal muscles while maintaining low or no activity in FSHD-unaffected tissues and (2) minimizing epigenetic regulators to their essential functional repressor domains, together creating enough space to include a single guide RNA (sgRNA) expression cassette within the AAV packaging limit. Targeting these AIO cargos to DUX4 suppressed pathogenic gene expression in FSHD1 and FSHD2 myocytes. Importantly, AAV-mediated delivery of our best AIO cargo also repressed DUX4 in an FSHD xenograft mouse model. These therapeutic cassettes represent a clinically relevant CRISPRi platform for gene therapy of FSHD and a useful proof-of-concept platform for other skeletal muscle gene therapies.
other
2026-08-05 | In vitro and in silico characterization of competitive inhibition and repression of DUX4 target gene activation as a therapeutic approach for facioscapulohumeral muscular dystrophy (FSHD)
ABSTRACT Facioscapulohumeral muscular dystrophy (FSHD) is a rare neuromuscular disease caused by aberrant re-expression of the embryonic transcription factor DUX4 in skeletal muscle, which activates a toxic transcriptional program that drives progressive muscle wasting. No approved disease-modifying therapies currently exist. Prior work in mammalian and zebrafish models has shown that a truncated form of DUX4 retaining only its DNA-binding domain (DBD) lacks transactivation capacity and can suppress DUX4-FL-driven pathology; separately, dCas9/KRAB-based epigenetic repressors have demonstrated efficacy in silencing DUX4 expression, though CRISPR-based strategies face challenges from the repetitive nature of the D4Z4 locus, the immunogenicity associated with bacterial Cas proteins, and the payload limitations of gene delivery vehicles. Building on these findings, we corroborate that the DUX4 DBD, comprising both homeodomains, acts as a non-toxic competitive inhibitor of full-length DUX4 (DUX4-FL) at its genomic target sites, and extend this strategy by fusing the DBD to a human KRAB(ZNF10) domain, converting DUX4 from a transcriptional activator into a fully humanized epigenetic silencer of its own targets. Using a fluorescent DUX4-responsive reporter, we show that DBD alone produces dose-dependent repression of DUX4-FL transcriptional activity in HEK293T cells (200-fold at the highest inducible dose tested), while a constitutively expressed DBD-KRAB fusion produces significantly greater repression than DBD alone (949-fold versus 17-fold at a 25x molar ratio), with a similar trend observed in C2C12 myoblasts (47-fold versus 3.3-fold knockdown). To contextualize these findings and explore dosing considerations, we developed three complementary computational models – a transcription factor competitive binding model, a myotube diffusion model, and an ordinary differential equation (ODE) compartmental model – that illustrate how DBD concentration, intracellular diffusion, and population-level cell state transitions may relate to therapeutic efficacy. Together, these results corroborate and extend existing approaches into a single, fully humanized construct that may help circumvent the immunogenicity and delivery limitations of Cas-based systems.
2024-02-04 | SMCHD1 activates the expression of genes required for the expansion of human myoblasts
ABSTRACT SMCHD1 is an epigenetic regulatory protein known to modulate the targeted repression of large chromatin domains. Diminished SMCHD1 function in muscle fibers causes Facioscapulohumeral Muscular Dystrophy (FSHD2) through derepression of the D4Z4 chromatin domain, an event which permits the aberrant expression of the disease-causing gene DUX4 . Given that SMCHD1 plays a broader role in establishing the cellular epigenome, we examined whether loss of SMCHD1 function might affect muscle homeostasis through additional mechanisms. Here we show that acute depletion of SMCHD1 results in a DUX4-independent defect in myoblast proliferation. Genomic and transcriptomic experiments determined that SMCHD1 associates with enhancers of genes controlling cell cycle to activate their expression. Amongst these cell cycle regulatory genes, we identified LAP2 as a key target of SMCHD1 required for the expansion of myoblasts, where the ectopic expression of LAP2 rescues the proliferation defect of SMCHD1-depleted cells. Thus, the epigenetic regulator SMCHD1 can play the role of a transcriptional co-activator for maintaining the expression of genes required for muscle progenitor expansion. This DUX4-independent role for SMCHD1 in myoblasts suggests that the pathology of FSHD2 may be a consequence of defective muscle regeneration in addition to the muscle wasting caused by spurious DUX4 expression. Chromatin modifier SMCHD1 regulates the proliferation of human myoblasts SMCHD1 binds to enhancers of cell cycle regulatory genes to activate their expression Lap2 is an SMCHD1 direct target gene that regulates the expansion of human myoblasts.
2022-07-14 | Multimodal Imaging Findings in Retinopathy Associated with Facioscapulohumeral Muscular Dystrophy before and after Treatment with Intravitreal Aflibercept and Laser Photocoagulation
A 52-year-old man with a history of facioscapulohumeral dystrophy (FSHD) and hypertension presented with decreased vision in his left eye (OS) of several weeks' duration. The best-corrected visual acuity was 1.0 in both eyes (OU), with fundus soft exudates in the right eye (OD) and exudative maculopathy OS. Optical coherence tomography (OCT) showed macular edema and hard exudates OS, and OCT angiography (OCTA) showed nonperfusion areas and arterial tortuosity OU and a capillary aneurysm OS. After photocoagulation of the nonperfusion areas OU and intravitreal injection of aflibercept OS, the macular edema OS decreased and subjective symptoms improved. However, the nonperfusion area OS was enlarged on OCTA. We report the OCTA findings before and after antivascular endothelial growth factor treatment in a patient with FSHD.
2022-04-27 | Antiapoptotic Protein FAIM2 is targeted by miR-3202, and DUX4 via TRIM21, leading to cell death and defective myogenesis.
Inappropriate expression of DUX4, a transcription factor that induces cell death at high levels of expression and impairs myoblast differentiation at low levels of expression, leads to the development of facioscapulohumeral muscular dystrophy (FSHD), however, the pathological mechanisms downstream of DUX4 responsible for muscle loss are poorly defined. We performed a screen of 1972 miR inhibitors for their ability to interfere with DUX4-induced cell death of human immortalized myoblasts. The most potent hit identified by the screen, miR-3202, is known to target the antiapoptotic protein FAIM2. Inhibition of miR-3202 led to the upregulation of FAIM2, and remarkably, expression of DUX4 led to reduced cellular levels of FAIM2. We show that the E3 ubiquitin ligase and DUX4 target gene, TRIM21, is responsible for FAIM2 degradation downstream of DUX4. Human myoblasts overexpressing FAIM2 showed increased resistance to DUX4-induced cell death, whereas in wild-type cells FAIM2 knockdown resulted in increased apoptosis and failure to differentiate into myotubes. The necessity of FAIM2 for myogenic differentiation of WT cells led us to test the effect of FAIM2 overexpression on the impairment of myogenesis by DUX4. Strikingly, FAIM2 overexpression rescued the myogenic differentiation defect caused by low-level expression of DUX4. These data implicate FAIM2 levels, modulated by DUX4 through TRIM21, as an important factor mediating the pathogenicity of DUX4, both in terms of cell viability and myogenic differentiation, and thereby open a new avenue of investigation towards drug targets in FSHD.
2022-04-16 | Randomized phase 2 study of ACE-083, a muscle-promoting agent, in facioscapulohumeral muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy without approved therapies. In this study we evaluated whether locally acting ACE-083 could safely increase muscle volume and improve functional outcomes in adults with FSHD.Participants were at least 18 years old and had FSHD1/FSHD2. Part 1 was open label, ascending dose, assessing safety and tolerability (primary objective). Part 2 was randomized, double-blind for 6 months, evaluating ACE-083240 mg/muscle vs placebo injected bilaterally every 3 weeks in the biceps brachii (BB) or tibialis anterior (TA) muscles, followed by 6 months of open label. Magnetic resonance imaging measures included total muscle volume (TMV; primary objective), fat fraction (FF), and contractile muscle volume (CMV). Functional measures included 6-minute walk test, 10-meter walk/run, and 4-stair climb (TA group), and performance of upper limb midlevel/elbow score (BB group). Strength, patient-reported outcomes (PROs), and safety were also evaluated.Parts 1 and 2 enrolled 37 and 58 participants, respectively. Among 55 participants evaluable in Part 2, the least-squares mean (90% confidence interval, analysis of covariance) treatment difference for TMV was 16.4% (9.8%-23.0%) in the BB group (P < .0001) and 9.5% (3.2%-15.9%) in the TA group (P = .01). CMV increased significantly in the BB and TA groups and FF decreased in the TA group. There were no consistent improvements in functional or PRO measures in either group. The most common adverse events were mild or moderate injection-site reactions.Significant increases in TMV with ACE-083 vs placebo did not result in consistent functional or PRO improvements with up to 12 months of treatment.
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Drug Discovery Landscape
18 orphan drug designations for Facioscapulohumeral dystrophy.
18 orphan drug designations for Facioscapulohumeral dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
apitegromab | antibodies | FDA | Scholar Rock, Inc. | |
double homeobox 4 -anti-sense oligonucleotide | oligonucleotides | FDA | — | Solve FSHD |
small molecule inhibitor of the DUX4 transcription factor | small molecules | FDA | — | Altay Therapeutics |
AAV-based gene therapy expressing artificial microRNA targeting the human DUX4 open reading frame | gene therapies | FDA | — | Armatus Bio |
Adeno-Associated Viral Vector Expressing Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/dCas-based Gene Therapy consisting of a Single Guide RNA targeting the Human D4Z4 Locus and a messenger RNA encoding dCasONYX | gene therapies | FDA | EpiCrispr Biotechnologies, Inc. | |
Humanised IgG1 monoclonal antibody against TfR1 conjugated to double stranded siRNA oligonucleotide against DUX4 mRNA via a non-cleavable linker | combination | EMA | MWB Consulting | |
An antibody oligonucleotide conjugate, comprised of a human transferrin receptor 1 targeting, effector function null, humanized IgG1 antibody, a MCC maleimide linker, and a double-stranded siRNA oligonucleotide targeting DUX4 | oligonucleotides | FDA | Avidity Biosciences, Inc. | |
nandrolone | small molecules | FDA | — | Sarcomed AB |
Losmapimod | small molecules | EMA | Sanofi B.V. | |
losmapimod | small molecules | FDA | Fulcrum Therapeutics, Inc. | |
Follistatin291-IgG2 Fc fusion protein | proteins | FDA | Acceleron Pharma Inc. | |
rebastinib | small molecules | FDA | — | Genea Biocells US Inc. |
Ascorbic acid | small molecules | EMA | — | Université de Montpellier |
Alpha-tocopherol | small molecules | EMA | — | Université de Montpellier |
L-selenomethionine | small molecules | EMA | — | Université de Montpellier |
Zinc gluconate | small molecules | EMA | — | Université de Montpellier |
recombinant human histidyl tRNA synthetase | proteins | FDA | aTyr Pharma, Inc. | |
Amino acids 2-506 of the wild-type human histidyl-tRNA synthetase [ATYR1940] | proteins | EMA | Voisin Consulting Life Sciences |
“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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