RARE DISEASE
Myotonic dystrophy
Myotonic dystrophy
Myotonic dystrophy
Drug discovery
8
drugs
With orphan designations
Overview
Myotonic dystrophy (DM) is an inherited multisystem disorder characterized by progressive muscle weakness, myotonia, cardiac conduction defects, and systemic manifestations affecting the eyes, endocrine system, and CNS. Two types exist: DM1 (CTG repeat in DMPK) and DM2 (CCTG repeat in CNBP). DM1 often presents with distal weakness, cataracts, and cognitive impairment, while DM2 features proximal weakness and milder cardiac involvement [1][11][16].
Therapies
Symptomatic management: Mexiletine for myotonia [1], CPAP for sleep apnea [3], pacemakers for cardiac arrhythmias [6]
Multidisciplinary care: Neurology, cardiology, pulmonology, and rehab medicine coordination [1][6]
Experimental approaches: CRISPRi gene therapy targeting DMPK shows promise in preclinical studies [18]
Categories: rare genetic diseases, rare neurological diseases
Research Papers
1,068 drug discovery papers about Myotonic dystrophy, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,068 drug discovery papers about Myotonic dystrophy, with 6 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-30 | CDK12 Inhibitors in Myotonic Dystrophy Type I
This study utilises QSAR models based on machine learning to predict the selectivity, lipophilicity, solubility, and efficacy of CDK12 inhibitors in treating myotonic dystrophy type 1 (DM1). This research aims to create docking, 2D-QSAR, and 3D-QSAR models employing a unique dataset of 660 compounds with consistent experimental data. These models will enable medicinal chemists to develop enhanced medications more efficiently and quickly than current trial-and-error methods.
2026-08-15 | An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.
Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.
2026-08-04 | A bitter melon natural compound ameliorates the myotonic dystrophy type 1 skeletal muscle phenotype in a sex-specific manner.
Myotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disease characterized by severe skeletal muscle dysfunction. The etiology of DM1 is primarily driven by RNA toxicity resulting from a gain-of-function mutation in DMPK mRNAs. Beyond this hallmark, DM1 is also characterized by the repression of the AMP-activated protein kinase (AMPK) pathway. Previous work has shown that targeting AMPK represents a novel therapeutic avenue for DM1. In this study, we investigated the therapeutic potential of novel AMPK activators derived from Momordica charantia (bitter melon). A screen of 26 bitter melon-derived compounds (BMCs) in C2C12 myotubes identified BMC-25 as a potent AMPK activator. Acute treatment of DM1 (HSALR) mice with BMC-25 induced an expected activation of AMPK in DM1 mice, while chronic treatment restored several DM1 histopathological features, including toxic ribonuclear foci. Interestingly, BMC-25 treatment induced distinct, sex-dependent molecular benefits. In female DM1 mice, BMC-25 treatment corrected the pattern of expression of RNA-binding proteins including CELF1, MBNL1, and Staufen1 in skeletal muscle and achieved a much greater correction of alternative splicing of multiple transcripts relative to their respective controls. In contrast, male DM1 mice exhibited very limited improvements in these parameters. Collectively, our findings indicate that sustained AMPK activation with BMC-25 confers multifaceted benefits to DM1 skeletal muscle by improving core DM1 pathogenic features in a sex-dependent manner. Finally, these results highlight the potential of natural compounds like BMCs as novel, promising and accessible therapeutics for the DM1 muscle pathology.
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.
2026-07-23 | HSP90 inhibition partially rescues alternative splicing dysregulation in cell models of myotonic dystrophy.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic diseases caused by the expression of toxic expansion RNAs that sequester muscleblind-like (MBNL) proteins, resulting in extensive alternative splicing dysregulation. Given that there are no current disease-modifying treatments for DM, we sought to identify compounds that rescue the underlying splicing dysregulation. A medium throughput splicing screen utilizing DM1 patient-derived fibroblasts was developed and used to screen 1584 compounds from the NIH NCI Diversity Set VI, leading to the identification of macbecin II, an HSP90 inhibitor. Macbecin II-mediated HSP90 inhibition corrects several MBNL-regulated splicing events in DM1 myotubes, and a structurally distinct HSP90 inhibitor, CCT018159, produces similar effects. Using RT-PCR splicing analysis, siRNA knockdown, RT-qPCR, immunoblotting, and RNA fluorescence in situ hybridization we examined the effects of HSP90 inhibition in DM models. HSP90 inhibition increases MBNL1 and MBNL2 transcript levels, increases MBNL2 protein, and reduces toxic CUG RNA and nuclear foci in DM1 cell models. An analysis of individual HSP90 isoforms reveals that knocking down HSP90AA1, HSP90AB1, and TRAP1 partially improves splicing defects, whereas HSP90B1 knockdown exacerbates mis-splicing. We also show that treatment with HSP90 inhibitors corrects mis-splicing in DM2 myotubes. Together, these data identify HSP90 as a modifier of RNA toxicity and alternative splicing in DM and support further evaluation of HSP90-directed therapeutic strategies.
proteins
2026-04-21 | dMyc suppresses CTG-induced cytotoxicity in the Drosophila model of DM1 by reducing autophagy and cell death.
Myotonic Dystrophy Type 1 (DM1) is a complex, genetic, and multisystemic disorder caused by the expansion of CTG trinucleotide repeats in the Dystrophia Myotonica Protein Kinase gene, leading to the formation of toxic RNA foci, which finally result in progressive muscle weakness, myotonia, and systemic complications affecting almost every organ system of the body. Despite its severity and high prevalence, effective therapeutic strategies remain elusive. Our study aims to identify a genetic modifier with therapeutic potential. We used transgenic flies expressing pathogenic CTG250 and CTG270 repeats as a Drosophila model of DM1, which recapitulated the hallmark features: formation of RNA foci, muscle fibre degeneration, impaired locomotor activity, and shortened lifespan. Drosophila Myc (dMyc), also known as diminutive, is a highly conserved transcription factor that plays a crucial role in cellular growth, metabolism, and autophagy. We found that targeted overexpression of dMyc significantly ameliorated disease phenotypes, including improved muscle integrity, enhanced motor function, extended lifespan, and reduced RNA foci. Our findings also revealed that dMyc expression is significantly reduced in flies with disease caused by abnormal CTG expansion. Overexpression of dMyc led to a marked decrease in autophagy and apoptosis. Our findings highlight impaired dMyc expression in CTG-mediated pathogenesis in the DM1 model and suggest that modulation of Myc expression could be a promising therapeutic intervention for DM1.
2026-04-20 | Distinct cellular effects of myotonic dystrophy type 2 repeat-associated non-AUG tetrapeptides.
Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystemic disorder caused by the expansion of CCTG repeats in the first intron of the CNBP gene. Repeat-associated non-AUG (RAN) translation of the expanded CCTG RNA generates two tetrapeptide repeat proteins, polyQAGR and polyLPAC, but their roles in DM2 pathogenesis remain unclear. To define their individual contributions, we expressed codon-optimized polyQAGR and polyLPAC peptides with an ATG start codon in Drosophila melanogaster. Expression of both tetrapeptide repeat proteins reduced viability and lifespan and induced eye degeneration and locomotor defects. We found that polyQAGR accumulated in the nucleolus, disrupted nucleolar integrity and impaired rRNA processing. It also interfered with autophagy, promoting Atg5 and Atg7 transcription and accumulation of Atg8a- and Ref(2)P-positive aggregates. Overexpression of Atg8a or Ref(2)P mitigated polyQAGR-induced eye toxicity, whereas knockdown of autophagy genes worsened it. Conversely, PolyLPAC expression increased the cytoplasmic pool of TIAR in human cells and in DM2 patient-derived myoblasts. Together, these findings show that polyQAGR and polyLPAC exert distinct toxic effects that likely converge to drive DM2 pathogenesis and may represent promising therapeutic targets.
2025-12-19 | Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy.
Myotonic dystrophy type 1 is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. Building on an established Drosophila model, we study the neuropathological features of the disease by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of CUG repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of CUG repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of fasII is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded CUG expression at the neuromuscular junction. In contrary, overexpression of FasII-A-PEST+ rescues the synaptic and behavioral defects. Our study provides insights into the fundamental mechanisms underlying synapse dysregulation in myotonic dystrophy type 1.
2025-04-16 | Pentatricopeptide repeat protein targeting CUG repeat RNA ameliorates RNA toxicity in a myotonic dystrophy type 1 mouse model.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by the expansion of a CTG-triplet repeat in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. It results in the transcription of toxic RNAs that contain expanded CUG repeats (CUGexp). Splicing factors, such as muscleblind-like 1 (MBNL1), are sequestered by CUGexp, thereby disrupting the normal splicing program that is essential for various cellular functions. Pentatricopeptide repeat (PPR) proteins, originally found in plants, regulate RNA in organelles by binding in a sequence-specific manner. Here, we designed PPR proteins that specifically bind to the hexamer of CUG repeat RNAs (CUG-PPRs) and showed that CUG-PPR1 could ameliorate RNA toxicity induced by CUGexp in cell models of DM1. A single systemic recombinant adeno-associated virus (AAV9) vector-mediated gene delivery of CUG-PPR1 demonstrated long-term therapeutic effects on myotonia and restored splicing activity in a mouse model of DM1. These results highlight the potential of PPR molecules to target pathogenic RNA sequences in DM1 and potentially other RNA-mediated disorders.
2025-01-24 | Co-opting MBNL-dependent alternative splicing cassette exons to control gene therapy in myotonic dystrophy
Abstract Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG repeat expansion that accumulate as toxic CUG repeat RNA. Functional sequestration of muscleblind-like (MBNL) proteins by CUG repeat RNA leads to deleterious, yet predictable changes in alternative splicing in DM. Genetic medicines for DM that reduce CUG repeat RNA or increase MBNL are advancing, but application of a viral-based approach must contend with high phenotypic and molecular variability. To address this, we have repurposed well-described cassette exons that are excluded by MBNL action to tune translational output of a therapeutic protein. We show that these splicing events can be taken out of genetic context and respond to changes in MBNL concentration or accumulation of toxic CUG repeat RNA, can deliver therapeutic MBNL1 protein to improve skeletal muscle myotonia or prevent cardiac toxicity associated with MBNL1 overexpression in mice, and distinguish DM patient-derived skeletal muscle myotubes from isogenic controls. Further work to fine-tune events to specific tissue targets and therapeutic cargos is needed, but these events can increase the therapeutic window for viral-based approaches for DM1.
oligonucleotides
2026-09-30 | Antisense Oligonucleotide-Mediated Degradation of Toxic RNA in Myotonic Dystrophy Type 1.
Myotonic dystrophy (DM) exists in two forms, type 1 (DM1) and type 2 (DM2), both inherited in an autosomal dominant manner and caused by toxic gain-of-function RNAs produced from unstable repeat expansions. In DM1, the mutation lies in the DMPK gene, whereas in DM2 it involves the CNBP gene. These repeats are inherently unstable, with a strong tendency to further expand in somatic tissues and across generations, driving disease progression and anticipation. Despite arising from distinct genetic defects, DM1 and DM2 share a common pathogenic pathway-RNA-mediated toxicity-which accounts for their overlapping clinical manifestations. Both are multisystemic disorders characterized by myotonia, early cataracts, and defects in cardiac conduction, alongside a range of additional systemic complications. To date, no curative therapy is available, and management remains largely symptomatic. Among experimental approaches, antisense oligonucleotide (AON) therapies-particularly gapmers-have emerged as one of the most promising strategies. Gapmers are designed to resist nuclease degradation and bind their targets with high affinity while still promoting RNase H-mediated cleavage of toxic transcripts, making them especially suitable for targeting nuclear-retained repeat RNAs. This chapter summarizes current progress in the development of gapmer-based AONs for DM1, highlighting both their therapeutic potential and the challenges that must be overcome for successful clinical translation.
2026-07-23 | Fatty-acid-based antimiR-23b delivery in the DMSXL model: A potential therapeutic strategy for brain dysfunction in myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder caused by CTG repeat expansions in the DMPK gene, leading to the formation of toxic RNA foci that sequester essential splicing regulators MBNL1/2. Beyond muscle impairment, DM1 affects also the brain, leading to significant cognitive deficits, behavioral abnormalities, and intellectual disabilities. This study evaluates the therapeutic potential of the lipid-conjugated antimiR-23b, X82108, designed to promote MBNL1/2 upregulation through inhibition of miR-23b. Systemic administration of X82108 in mice and non-human primates efficiently crosses the blood-brain barrier, increasing MBNL1 in the brain. In DMSXL transgenic mice, treatment increases Mbnl1/2, reduces toxic DMPK, and restores normal splicing patterns across all brain regions. These molecular improvements correlate with improved behavioral outcomes, including reduced impulsivity and normalized exploratory activity. Collectively, the findings highlight X82108 as a promising systemic therapy for DM1, targeting not only muscular features as we have previously shown but also DM1-related CNS alterations.
2026-06-16 | Therapeutic Innovation, Clinical Trial Acceleration, and Lifestyle Interventions in Myotonic Dystrophy Type 1: A Systematic Review
Therapeutic development in myotonic dystrophy type 1 (DM1) has accelerated in recent years, with a near doubling of clinical trials and expansion into late-stage development. The therapeutic landscape has diversified to include small molecules, oligonucleotide-based therapies, antibody-oligonucleotide conjugates, gene therapies, and microRNA-targeting strategies. Nucleic acid- based approaches have shown promising target engagement and early clinical signals, supporting their potential for disease modification. In parallel, preclinical avances. and non-pharmacological interventions such as exercise and rehabilitation are broadening the therapeutic scope. Overall, DM1 research is entering a more mature phase with multiole conversing therapeutic strategies.
2026-05-21 | Enhanced antisense oligonucleotide delivery reveals that transcript turnover impacts apparent splicing rescue in myotonic dystrophy.
Steric-blocking antisense oligonucleotides rescue myotonic dystrophy type 1 phenotypes in preclinical models and are under evaluation in clinical trials. However, the rationale for biomarker selection remains a topic of debate. Here, we show that a cyclic cell-penetrating peptide that escapes endosomes enhances muscle delivery of a phosphorodiamidate morpholino oligonucleotide designed to block pathogenic CUG repeat expansions in HSALR mice. A single systemic administration rescued mis-splicing and eliminated myotonia 1 week post-injection, with partial splicing rescue evident after 24 h. Interestingly, some exons showed more robust rescue than others, but the relationship between muscleblind-like (MBNL) protein concentration ([MBNL]) and percent spliced in (Ψ) did not fully explain the extent of rescue. We hypothesized that since pre-existing transcripts must be degraded to reveal the full drug effect, rates of transcript replacement might account for these discrepancies. We formulated a mathematical framework and used Bayesian inference to model how apparent Ψ lags behind nascent Ψ as a function of time; faster rates of replacement result in shorter lags. In vivo 5-ethynyl uridine labeling followed by RNA sequencing (RNA-seq) validated these predictions. Overall, we show that transcript turnover influences Ψ during periods of dynamically changing [MBNL] and recommend considering this when selecting splicing biomarkers and interpreting responses to therapeutic interventions.
2026-04-03 | Muscleblind-like proteins dimerize by forming disulfide bonds to regulate alternative splicing and pathogenic RNA foci formation.
Muscleblind-like (MBNL) RNA-binding proteins (RBPs) possess modular domains that mediate regulation of alternative splicing and RNA localization. Myotonic Dystrophy Type 1 is a CTG repeat expansion disorder where MBNL is sequestered into intranuclear RNA foci, impairing its function. Previous studies found that MBNL self-associates through its exon 7, but the nature of this interaction is not well understood. We identified a cysteine in MBNL1 exon 7 that enables dimerization through formation of an intermolecular disulfide bond. We likewise demonstrate that MBNL2 dimerizes by forming disulfide bonds between multiple cysteines in its carboxy-terminus. Nucleocytoplasmic fractionation revealed a greater proportion of MBNL1 dimer in the nucleus, suggesting a nuclear function for the MBNL1 dimer. We investigated a connection between MBNL1 dimerization and MBNL1-mediated regulation of alternative splicing. To accomplish this, we mutated the MBNL1 cysteine in question to alanine (C325A) and performed RNAseq. We uncovered novel splicing events sensitive to MBNL1 dimerization. We also found that MBNL1 C325A, when co-expressed with expanded CTG repeats, produces smaller, more numerous foci, suggesting a role for the MBNL1 dimer in maintaining foci integrity. These results provide insight into biological and pathological mechanisms of MBNL1 dimerization and suggest other RBPs might similarly dimerize to regulate function.
gene therapies
2026-08-21 | CRISPR/dCas9-mediated tuning of DMPK transcription reveals a quantitative relationship between toxic repeat RNA expression and MBNL1 activity in myotonic dystrophy.
Myotonic dystrophy type 1 (DM1) is caused by (CUG)n-expanded DMPK transcripts that sequester the splicing factor MBNL1 in the nucleus, resulting in widespread splicing abnormalities. Although significant progress has been made in understanding DM1 pathogenesis, the contribution of DMPK transcript levels to disease severity, and the variability of these levels across cell types, tissues, and patients, remains poorly understood. To investigate this in a quantitative manner, we developed isogenic human immortalized myoblast models with inducible modulation of DMPK RNA levels using CRISPR activation (CRISPRa) and interference (CRISPRi) guided by synthetic sgRNAs. CRISPRa elevated DMPK RNA levels by more than three-fold, intensifying MBNL1-dependent splicing defects. In contrast, CRISPRi reduced DMPK RNA expression by approximately 80%, partially rescuing splicing abnormalities. These changes were validated by visualizing (CUG)n foci using RNA FISH. Lowering DMPK transcript levels increased the availability of free nucleoplasmic MBNL1, whereas upregulation further depleted MBNL1, reinforcing the central role of MBNL1 sequestration in repeat RNA toxicity. Our findings demonstrate that expanded DMPK transcript levels modulate free MBNL1 concentration and alternative splicing in a dose-dependent manner, underscoring the central role of repeat RNA expression in DM1 pathogenesis. These models provide a powerful platform for dissecting variability in DMPK expression and for defining the therapeutic thresholds required for effective DMPK knockdown, thereby offering critical insights for the design and evaluation of DMPK and MBNL1-directed therapeutic strategies.
2026-07-10 | Aberrant neuronal differentiation and splicing defects in Congenital Myotonic Dystrophy (DM1) iPSC models.
Myotonic Dystrophy type 1 (DM1) is an autosomal multisystem disorder manifested due to unstable CTG nucleotide repeat expansion within the 3'-untranslated region of the dystrophia myotonica protein kinase ( DMPK ) gene. Although progress towards understanding of molecular pathogenesis in muscle and heart has been made, the pathways that affect the brain in DM1 is fundamentally unknown. In addition, the congenital DM1 manifest even more complicated brain abnormalities. Despite the wealth of existing cellular and animal models, iPSCs based studies are being fostered as they replicate the human model more closely to the disease. In view of this context, we set out to characterize the differentiation potential of congenital DM1 patient derived iPSC lines towards neuronal cells. Using neurogenin2 (NGN2) induced direct reprogramming of iPSCs into neurons and chemically defined media-induced neural induction protocol, we find that congenital DM1 mutant iPSC derived neurons exhibited precocious differentiation, as evidenced by their expression of pan-neuronal markers TUJ1 and Map2, along with increased processes extension and neurite length. Moreover, unbiased RNA sequencing analyses and qPCR validation revealed precocious and enhanced expression of several neurogenic transcription factors including, Ascl1, NeuroG2, and NeuroD1. Furthermore, immunofluorescence imaging of MBNL1 and MBNL2, RNA-splicing factors, displayed enhanced nuclear aggregations, a hallmark of the DM1 disease, in the mutant lines. Moreover, investigation of RNA splicing events identified mis-splicing in many important genes/transcripts including RMST, ANK3 and MBD1 during the neural conversion of congenital DM1 lines. These studies reveal novel paradigms that may contribute to neurological pathogenesis in CDM1 patients. These studies also provide a strong foundation for future mechanistic investigation aimed at understanding CDM1 pathology and may open new avenues for the development of gene therapy approaches for individuals with DM1.
2026-07-09 | Elimination of myotonia improves myopathy in a muscleblind-like knockout model of myotonic dystrophy.
A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1.
2026-06-25 | Generation of isogenic rescue iPSC lines by targeted CTG-repeat excision for myotonic dystrophy type 1.
An expanded CTG repeat in the Dystrophia Myotonica Protein Kinase (DMPK) gene is associated with myotonic dystrophy type 1 (DM1), an autosomal dominant neuromuscular disorder characterised by progressive muscle weakness, myotonia, cognitive decline, and a variety of other manifestations. Here, we report the generation of isogenic induced pluripotent stem cell (iPSC) lines, derived from patient DM1 iPSC lines carrying varying expanded (CTG)n repeats in DMPK. These gene-edited isogenic iPSC lines, in which the pathogenic repeat has been excised, serve as a reference for assessing DM1-associated phenotypes in relevant differentiated cell types, such as muscle progenitor cells and neurons.
2026-04-18 | Therapeutic Strategies Targeting the Molecular Pathogenesis of Myotonic Dystrophy Type 1: Current Status and Future Directions.
Myotonic dystrophy type 1 is the most prevalent adult-onset muscular dystrophy and is characterized by progressive muscle weakness, myotonia, cardiac conduction defects, endocrine dysfunction, and central nervous system involvement. Myotonic dystrophy type 1 is caused by an unstable CTG repeat expansion in the 3' untranslated region of the DMPK gene, which produces toxic CUG-expanded transcripts that sequester RNA-binding proteins such as Muscleblind-like, induce widespread alternative splicing defects, and drive an RNA gain-of-function mechanism rather than simple DMPK haploinsufficiency. Despite major advances in understanding the molecular pathogenesis of myotonic dystrophy type 1, there is still no approved cure or disease-modifying therapy. This review summarizes the molecular basis of myotonic dystrophy type 1 and provides an in-depth overview of emerging therapeutic strategies that directly target the underlying pathogenic cascade at the DNA and RNA levels. Gene therapy-based approaches, including CRISPR-mediated genome editing, aim to reduce or eliminate the expanded CTG repeats or expanded DMPK allele and its toxic transcripts. In parallel, a broad spectrum of RNA-directed interventions is being developed, encompassing antisense oligonucleotides, antibody-penetrating and cell-penetrating peptide-conjugated antisense oligonucleotides to enhance skeletal and cardiac muscle delivery, small interfering RNAs, and microRNA-based tools such as antagomiRs. Additional strategies exploit engineered RNA-binding proteins and peptide decoys to disrupt toxic ribonuclear aggregates, polyadenylation signal-driven premature transcriptional termination to selectively silence mutant DMPK, and small molecules that modulate RNA metabolism, dissolve CUG RNA foci, or correct downstream mis-splicing. By integrating data from preclinical models and ongoing clinical trials, including recent advances with muscle‑targeted antisense oligonucleotide conjugates and gene therapy, this review outlines the current status, strengths, and limitations of these mechanism-based therapies for myotonic dystrophy type 1. The discussion highlights key translational challenges such as efficient delivery to skeletal muscle, the heart, and brain, long-term safety, and robust pharmacodynamic biomarkers as well as opportunities for combination and next-generation approaches aimed at converting molecular correction into durable clinical benefit for patients with myotonic dystrophy type 1.
other
2026-03-13 | Delpacibart etedesiran improves the molecular pathology of myotonic dystrophy type 1 in the phase 1/2 MARINA study.
Myotonic dystrophy type 1 (DM1) is a rare, autosomal dominant, progressive neuromuscular disease caused by the expansion of CTG repeats in the DM1 protein kinase (DMPK) gene. Expanded CUG repeats in the mutant DMPK transcript bind and sequester splicing factors, especially in the muscleblind-like (MBNL) family, leading to misregulated alternative splicing of mRNA, which is the main driver of DM1 pathology. We designed an antibody-oligonucleotide conjugate (AOC), delpacibart etedesiran (del-desiran), to deliver a DMPK-targeting small interfering RNA to muscle via transferrin receptor 1-mediated cell internalization. Del-desiran reduced mutDMPK mRNA expression, increased estimated levels of functional MBNL, and corrected disease-associated mis-splicing in a dose-dependent manner. The extent of increase in functional MBNL was associated with consistent trends toward muscle function improvement, confirming del-desiran's mechanism of action and supporting its development as a treatment for DM1. The translation of its pharmacodynamic activity from preclinical models (patient-derived myotubes and Macaca fascicularis [cynomolgus monkeys]) to patients with DM1 demonstrates del-desiran's consistency across species and reveals the potential broad utility of the AOC platform in further neuromuscular diseases.
2026-03-02 | The Usage and Limitations of Gene Therapy Versus Stem Cell Therapy for Myotonic Dystrophy Type 1 (DM1): Special Focus on Immune Response
Muscular dystrophies include myotonic dystrophy (MD). Although there is no cure for this disorder, many treatments can manage symptoms and reduce disease development. Standard pharmacological treatments and rehabilitation methods have largely failed, prompting researchers to investigate stem cell and gene therapy options. This review will discuss gene therapy and stem cell therapy as adjuvant therapies for MD, including their benefits, drawbacks, and timeline for implementation. We searched PubMed, Scopus, Web of Science (WOS), Cochrane Library, and Embase from 1980 to 2024 for preclinical and clinical gene therapy papers for MD using keywords such as "myotonic dystrophy" and "gene therapy." A search for "myotonic dystrophy" and "Stem Cell" yielded studies on stem cell treatment for MD. The initial search found 50 gene therapy and 38 stem cell research articles. Following our exclusion and filtering criteria, we deleted 31 articles on gene therapy and 23 articles on stem cells. We found 19 gene therapy publications and 15 stem cell-based publications. Antisense oligonucleotides (ASO), CRISPR technology, and AAV vectors have become the most popular methods. Induced pluripotent stem cells (iPSCs) and muscle-derived progenitor cells (MuSCs) were important cellular sources for investigation or application. Most research focuses on myotonic dystrophy type I (DM1). It is widely established that AAV vector-induced immune responses can affect the safety and efficacy of genetic therapy. Specific stem cells may also modulate MD patients' immunological responses, improving prognosis. Using cytokines and monoclonal antibodies as adjuvants to treat this complex illness is becoming more common.
2024-11-18 | in vivo-like Scaffold-free 3D in vitro Models of Muscular Dystrophies: The Case for Anchored Cell Sheet Engineering in Personalized Medicine
Abstract Progress in understanding the underlying mechanisms of muscle dystrophies and finding effective treatments for them has been hindered by the absence of relevant in vitro models for biomedical research. In this study, an entirely scaffold-free cell sheet engineering-based platform is used to make such in vitro models using patient-specific cells. Unlike reductionist bottom-up approaches, this holistic biofabrication method, termed anchored cell sheet engineering, effectively replicated mature cell phenotypes and tissue- and disease-specific ECM deposited by the cells themselves. Robust anchored 3D muscle fibers were developed using primary cells from both healthy individuals and patients with Duchenne dystrophy and Myotonic dystrophy type 1. Through a combination of histology, immunostaining, and proteomics analysis, it was demonstrated that these models formed mature constructs that closely resembled in vivo conditions, outperforming traditional 2D cultures in their translation potential. Models of diseased tissues, analyzed through various analysis, accurately reflected key phenotypic features of the respective diseases. Furthermore, when treated with therapeutically beneficial drugs, the detailed changes in their proteomic profiles were documented. This novel in vitro modeling approach, compared to other 3D techniques that use exogenous scaffolding or bioink, provides a promising platform for advancing the development of muscle dystrophy models, among other conditions.
2024-11-13 | Longitudinal Course of Myotonic Dystrophy Type 1 With Gait Training Using a Hybrid Assistive Limb: A Case Report.
Muscle dystrophy type 1 is the most common form of muscular dystrophy and is characterized by progressive distal dominant muscle weakness, muscle atrophy, and myotonic phenomena. Patients with progressive neuromuscular diseases such as myotonic dystrophy type 1 are prone to muscle weakness, movement disorders, and fatigue due to their underlying disease, which may limit their physical activity and ambulation. Six courses of gait training with a hybrid assistive limb (HAL) were performed in an adult male with myotonic dystrophy type 1 over 4.5 years. The two-minute walking distance and knee joint strength tended to increase, and the Timed Up and Go test time tended to decrease with gait training with HAL before and after each intervention. In the long term, the two-minute walking distance decreased slowly, but the Timed Up and Go and knee joint strength tended to be maintained. Functional ambulation category and activities of daily living levels were also maintained. These results suggest that intermittent gait training may be an effective rehabilitation method for maintaining gait independence and activities of daily living in patients with myotonic dystrophy type 1. The frequency and number of interventions should be considered for further effectiveness.
2024-09-15 | Ameliorated cellular hallmarks of myotonic dystrophy in hybrid myotubes from patient and unaffected donor cells.
Cell-based strategies are being explored as a therapeutic option for muscular dystrophies, using a variety of cell types from different origin and with different characteristics. Primary pericytes are multifunctional cells found in the capillary bed that exhibit stem cell-like and myogenic regenerative properties. This unique combination allows them to be applied systemically, presenting a promising opportunity for body-wide muscle regeneration. We previously reported the successful isolation of ALP+ pericytes from skeletal muscle of patients with myotonic dystrophy type 1 (DM1). These pericytes maintained normal growth parameters and myogenic characteristics in vitro despite the presence of nuclear (CUG)n RNA foci, the cellular hallmark of DM1. Here, we examined the behaviour of DM1 pericytes during myogenic differentiation. DMPK (CTG)n repeat lengths in patient pericytes were assessed using small pool PCR, to be able to relate variation in myogenic properties and disease hallmarks to repeat expansion. Pericytes from unaffected controls and DM1 patients were cultured under differentiating conditions in vitro. In addition, the pericytes were grown in co-cultures with myoblasts to examine their regenerative capacity by forming hybrid myotubes. Finally, the effect of pericyte fusion on DM1 disease hallmarks was investigated. Small pool PCR analysis revealed the presence of somatic mosaicism in pericyte cell pools. Upon differentiation to myotubes, DMPK expression was upregulated, leading to an increase in nuclear foci sequestering MBNL1 protein. Remarkably, despite the manifestation of these disease biomarkers, patient-derived pericytes demonstrated myogenic potential in co-culture experiments comparable to unaffected pericytes and myoblasts. However, only the unaffected pericytes improved the disease hallmarks in hybrid myotubes. From 20% onwards, the fraction of unaffected nuclei in myotubes positively correlated with a reduction of the number of RNA foci and an increase in the amount of free MBNL1. Fusion of only a limited number of unaffected myogenic precursors to DM1 myotubes already ameliorates cellular disease hallmarks, offering promise for the development of cell transplantation strategies to lower disease burden.
small molecules
2026-08-30 | CDK12 Inhibitors in Myotonic Dystrophy Type I
This study utilises QSAR models based on machine learning to predict the selectivity, lipophilicity, solubility, and efficacy of CDK12 inhibitors in treating myotonic dystrophy type 1 (DM1). This research aims to create docking, 2D-QSAR, and 3D-QSAR models employing a unique dataset of 660 compounds with consistent experimental data. These models will enable medicinal chemists to develop enhanced medications more efficiently and quickly than current trial-and-error methods.
2026-08-15 | An Ultrastructural and Proteomic Analysis in DM1 Young Adults' Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement.
Myotonic dystrophy type 1 (DM1) is a progressive muscular disorder caused by the expansion of CTG repeats in the 3' UTR of the DMPK gene. Although the pathogenic mechanisms remain unclear, recent evidence suggests that activation of innate immune responses may contribute to disease progression. In this study, we examined the ultrastructure and proteomic data of myoblasts from young adult DM1 patients carrying approximately 800 and 1300 CTG repeats in order to investigate a link between cellular stress and immune activation. We observed activation of the type I interferon (IFN-I) pathway associated with rough endoplasmic reticulum stress (sRER). The sRER response is likely triggered by the accumulation of toxic RNA species generated from the expanded DMPK allele. Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling. These findings support a model in which innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.
2026-08-04 | A bitter melon natural compound ameliorates the myotonic dystrophy type 1 skeletal muscle phenotype in a sex-specific manner.
Myotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disease characterized by severe skeletal muscle dysfunction. The etiology of DM1 is primarily driven by RNA toxicity resulting from a gain-of-function mutation in DMPK mRNAs. Beyond this hallmark, DM1 is also characterized by the repression of the AMP-activated protein kinase (AMPK) pathway. Previous work has shown that targeting AMPK represents a novel therapeutic avenue for DM1. In this study, we investigated the therapeutic potential of novel AMPK activators derived from Momordica charantia (bitter melon). A screen of 26 bitter melon-derived compounds (BMCs) in C2C12 myotubes identified BMC-25 as a potent AMPK activator. Acute treatment of DM1 (HSALR) mice with BMC-25 induced an expected activation of AMPK in DM1 mice, while chronic treatment restored several DM1 histopathological features, including toxic ribonuclear foci. Interestingly, BMC-25 treatment induced distinct, sex-dependent molecular benefits. In female DM1 mice, BMC-25 treatment corrected the pattern of expression of RNA-binding proteins including CELF1, MBNL1, and Staufen1 in skeletal muscle and achieved a much greater correction of alternative splicing of multiple transcripts relative to their respective controls. In contrast, male DM1 mice exhibited very limited improvements in these parameters. Collectively, our findings indicate that sustained AMPK activation with BMC-25 confers multifaceted benefits to DM1 skeletal muscle by improving core DM1 pathogenic features in a sex-dependent manner. Finally, these results highlight the potential of natural compounds like BMCs as novel, promising and accessible therapeutics for the DM1 muscle pathology.
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.
2026-07-23 | HSP90 inhibition partially rescues alternative splicing dysregulation in cell models of myotonic dystrophy.
Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic diseases caused by the expression of toxic expansion RNAs that sequester muscleblind-like (MBNL) proteins, resulting in extensive alternative splicing dysregulation. Given that there are no current disease-modifying treatments for DM, we sought to identify compounds that rescue the underlying splicing dysregulation. A medium throughput splicing screen utilizing DM1 patient-derived fibroblasts was developed and used to screen 1584 compounds from the NIH NCI Diversity Set VI, leading to the identification of macbecin II, an HSP90 inhibitor. Macbecin II-mediated HSP90 inhibition corrects several MBNL-regulated splicing events in DM1 myotubes, and a structurally distinct HSP90 inhibitor, CCT018159, produces similar effects. Using RT-PCR splicing analysis, siRNA knockdown, RT-qPCR, immunoblotting, and RNA fluorescence in situ hybridization we examined the effects of HSP90 inhibition in DM models. HSP90 inhibition increases MBNL1 and MBNL2 transcript levels, increases MBNL2 protein, and reduces toxic CUG RNA and nuclear foci in DM1 cell models. An analysis of individual HSP90 isoforms reveals that knocking down HSP90AA1, HSP90AB1, and TRAP1 partially improves splicing defects, whereas HSP90B1 knockdown exacerbates mis-splicing. We also show that treatment with HSP90 inhibitors corrects mis-splicing in DM2 myotubes. Together, these data identify HSP90 as a modifier of RNA toxicity and alternative splicing in DM and support further evaluation of HSP90-directed therapeutic strategies.
proteins
2026-04-21 | dMyc suppresses CTG-induced cytotoxicity in the Drosophila model of DM1 by reducing autophagy and cell death.
Myotonic Dystrophy Type 1 (DM1) is a complex, genetic, and multisystemic disorder caused by the expansion of CTG trinucleotide repeats in the Dystrophia Myotonica Protein Kinase gene, leading to the formation of toxic RNA foci, which finally result in progressive muscle weakness, myotonia, and systemic complications affecting almost every organ system of the body. Despite its severity and high prevalence, effective therapeutic strategies remain elusive. Our study aims to identify a genetic modifier with therapeutic potential. We used transgenic flies expressing pathogenic CTG250 and CTG270 repeats as a Drosophila model of DM1, which recapitulated the hallmark features: formation of RNA foci, muscle fibre degeneration, impaired locomotor activity, and shortened lifespan. Drosophila Myc (dMyc), also known as diminutive, is a highly conserved transcription factor that plays a crucial role in cellular growth, metabolism, and autophagy. We found that targeted overexpression of dMyc significantly ameliorated disease phenotypes, including improved muscle integrity, enhanced motor function, extended lifespan, and reduced RNA foci. Our findings also revealed that dMyc expression is significantly reduced in flies with disease caused by abnormal CTG expansion. Overexpression of dMyc led to a marked decrease in autophagy and apoptosis. Our findings highlight impaired dMyc expression in CTG-mediated pathogenesis in the DM1 model and suggest that modulation of Myc expression could be a promising therapeutic intervention for DM1.
2026-04-20 | Distinct cellular effects of myotonic dystrophy type 2 repeat-associated non-AUG tetrapeptides.
Myotonic dystrophy type 2 (DM2) is an autosomal dominant, multisystemic disorder caused by the expansion of CCTG repeats in the first intron of the CNBP gene. Repeat-associated non-AUG (RAN) translation of the expanded CCTG RNA generates two tetrapeptide repeat proteins, polyQAGR and polyLPAC, but their roles in DM2 pathogenesis remain unclear. To define their individual contributions, we expressed codon-optimized polyQAGR and polyLPAC peptides with an ATG start codon in Drosophila melanogaster. Expression of both tetrapeptide repeat proteins reduced viability and lifespan and induced eye degeneration and locomotor defects. We found that polyQAGR accumulated in the nucleolus, disrupted nucleolar integrity and impaired rRNA processing. It also interfered with autophagy, promoting Atg5 and Atg7 transcription and accumulation of Atg8a- and Ref(2)P-positive aggregates. Overexpression of Atg8a or Ref(2)P mitigated polyQAGR-induced eye toxicity, whereas knockdown of autophagy genes worsened it. Conversely, PolyLPAC expression increased the cytoplasmic pool of TIAR in human cells and in DM2 patient-derived myoblasts. Together, these findings show that polyQAGR and polyLPAC exert distinct toxic effects that likely converge to drive DM2 pathogenesis and may represent promising therapeutic targets.
2025-12-19 | Pre- and postsynaptic upregulation of FasII synergistically underlies neuropathological and behavioral phenotypes in a Drosophila model of myotonic dystrophy.
Myotonic dystrophy type 1 is a multisystemic disorder that has been extensively studied for decades, yet our understanding of its neuropathological aspect remains rudimentary. Building on an established Drosophila model, we study the neuropathological features of the disease by expressing untranslated expanded CUG repeats at the Drosophila larval neuromuscular junction. In this model, we show that both pre- and postsynaptic expressions of CUG repeats participate in inducing phenotypes in synaptic boutons, arbors, transmission and larval locomotor activity. Furthermore, expression of CUG repeats in either motorneurons or body wall muscles induces upregulation of the cell adhesion molecule FasII (NCAM1 in mammals), and the knockdown of fasII is sufficient to rescue the phenotypes. Overexpression of FasII-C, a FasII isoform with no cytoplasmic domain, mimics the phenotypes of expanded CUG expression at the neuromuscular junction. In contrary, overexpression of FasII-A-PEST+ rescues the synaptic and behavioral defects. Our study provides insights into the fundamental mechanisms underlying synapse dysregulation in myotonic dystrophy type 1.
2025-04-16 | Pentatricopeptide repeat protein targeting CUG repeat RNA ameliorates RNA toxicity in a myotonic dystrophy type 1 mouse model.
Myotonic dystrophy type 1 (DM1) is an autosomal dominant multisystemic disorder caused by the expansion of a CTG-triplet repeat in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. It results in the transcription of toxic RNAs that contain expanded CUG repeats (CUGexp). Splicing factors, such as muscleblind-like 1 (MBNL1), are sequestered by CUGexp, thereby disrupting the normal splicing program that is essential for various cellular functions. Pentatricopeptide repeat (PPR) proteins, originally found in plants, regulate RNA in organelles by binding in a sequence-specific manner. Here, we designed PPR proteins that specifically bind to the hexamer of CUG repeat RNAs (CUG-PPRs) and showed that CUG-PPR1 could ameliorate RNA toxicity induced by CUGexp in cell models of DM1. A single systemic recombinant adeno-associated virus (AAV9) vector-mediated gene delivery of CUG-PPR1 demonstrated long-term therapeutic effects on myotonia and restored splicing activity in a mouse model of DM1. These results highlight the potential of PPR molecules to target pathogenic RNA sequences in DM1 and potentially other RNA-mediated disorders.
2025-01-24 | Co-opting MBNL-dependent alternative splicing cassette exons to control gene therapy in myotonic dystrophy
Abstract Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by a CTG repeat expansion that accumulate as toxic CUG repeat RNA. Functional sequestration of muscleblind-like (MBNL) proteins by CUG repeat RNA leads to deleterious, yet predictable changes in alternative splicing in DM. Genetic medicines for DM that reduce CUG repeat RNA or increase MBNL are advancing, but application of a viral-based approach must contend with high phenotypic and molecular variability. To address this, we have repurposed well-described cassette exons that are excluded by MBNL action to tune translational output of a therapeutic protein. We show that these splicing events can be taken out of genetic context and respond to changes in MBNL concentration or accumulation of toxic CUG repeat RNA, can deliver therapeutic MBNL1 protein to improve skeletal muscle myotonia or prevent cardiac toxicity associated with MBNL1 overexpression in mice, and distinguish DM patient-derived skeletal muscle myotubes from isogenic controls. Further work to fine-tune events to specific tissue targets and therapeutic cargos is needed, but these events can increase the therapeutic window for viral-based approaches for DM1.
oligonucleotides
2026-09-30 | Antisense Oligonucleotide-Mediated Degradation of Toxic RNA in Myotonic Dystrophy Type 1.
Myotonic dystrophy (DM) exists in two forms, type 1 (DM1) and type 2 (DM2), both inherited in an autosomal dominant manner and caused by toxic gain-of-function RNAs produced from unstable repeat expansions. In DM1, the mutation lies in the DMPK gene, whereas in DM2 it involves the CNBP gene. These repeats are inherently unstable, with a strong tendency to further expand in somatic tissues and across generations, driving disease progression and anticipation. Despite arising from distinct genetic defects, DM1 and DM2 share a common pathogenic pathway-RNA-mediated toxicity-which accounts for their overlapping clinical manifestations. Both are multisystemic disorders characterized by myotonia, early cataracts, and defects in cardiac conduction, alongside a range of additional systemic complications. To date, no curative therapy is available, and management remains largely symptomatic. Among experimental approaches, antisense oligonucleotide (AON) therapies-particularly gapmers-have emerged as one of the most promising strategies. Gapmers are designed to resist nuclease degradation and bind their targets with high affinity while still promoting RNase H-mediated cleavage of toxic transcripts, making them especially suitable for targeting nuclear-retained repeat RNAs. This chapter summarizes current progress in the development of gapmer-based AONs for DM1, highlighting both their therapeutic potential and the challenges that must be overcome for successful clinical translation.
2026-07-23 | Fatty-acid-based antimiR-23b delivery in the DMSXL model: A potential therapeutic strategy for brain dysfunction in myotonic dystrophy type 1.
Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder caused by CTG repeat expansions in the DMPK gene, leading to the formation of toxic RNA foci that sequester essential splicing regulators MBNL1/2. Beyond muscle impairment, DM1 affects also the brain, leading to significant cognitive deficits, behavioral abnormalities, and intellectual disabilities. This study evaluates the therapeutic potential of the lipid-conjugated antimiR-23b, X82108, designed to promote MBNL1/2 upregulation through inhibition of miR-23b. Systemic administration of X82108 in mice and non-human primates efficiently crosses the blood-brain barrier, increasing MBNL1 in the brain. In DMSXL transgenic mice, treatment increases Mbnl1/2, reduces toxic DMPK, and restores normal splicing patterns across all brain regions. These molecular improvements correlate with improved behavioral outcomes, including reduced impulsivity and normalized exploratory activity. Collectively, the findings highlight X82108 as a promising systemic therapy for DM1, targeting not only muscular features as we have previously shown but also DM1-related CNS alterations.
2026-06-16 | Therapeutic Innovation, Clinical Trial Acceleration, and Lifestyle Interventions in Myotonic Dystrophy Type 1: A Systematic Review
Therapeutic development in myotonic dystrophy type 1 (DM1) has accelerated in recent years, with a near doubling of clinical trials and expansion into late-stage development. The therapeutic landscape has diversified to include small molecules, oligonucleotide-based therapies, antibody-oligonucleotide conjugates, gene therapies, and microRNA-targeting strategies. Nucleic acid- based approaches have shown promising target engagement and early clinical signals, supporting their potential for disease modification. In parallel, preclinical avances. and non-pharmacological interventions such as exercise and rehabilitation are broadening the therapeutic scope. Overall, DM1 research is entering a more mature phase with multiole conversing therapeutic strategies.
2026-05-21 | Enhanced antisense oligonucleotide delivery reveals that transcript turnover impacts apparent splicing rescue in myotonic dystrophy.
Steric-blocking antisense oligonucleotides rescue myotonic dystrophy type 1 phenotypes in preclinical models and are under evaluation in clinical trials. However, the rationale for biomarker selection remains a topic of debate. Here, we show that a cyclic cell-penetrating peptide that escapes endosomes enhances muscle delivery of a phosphorodiamidate morpholino oligonucleotide designed to block pathogenic CUG repeat expansions in HSALR mice. A single systemic administration rescued mis-splicing and eliminated myotonia 1 week post-injection, with partial splicing rescue evident after 24 h. Interestingly, some exons showed more robust rescue than others, but the relationship between muscleblind-like (MBNL) protein concentration ([MBNL]) and percent spliced in (Ψ) did not fully explain the extent of rescue. We hypothesized that since pre-existing transcripts must be degraded to reveal the full drug effect, rates of transcript replacement might account for these discrepancies. We formulated a mathematical framework and used Bayesian inference to model how apparent Ψ lags behind nascent Ψ as a function of time; faster rates of replacement result in shorter lags. In vivo 5-ethynyl uridine labeling followed by RNA sequencing (RNA-seq) validated these predictions. Overall, we show that transcript turnover influences Ψ during periods of dynamically changing [MBNL] and recommend considering this when selecting splicing biomarkers and interpreting responses to therapeutic interventions.
2026-04-03 | Muscleblind-like proteins dimerize by forming disulfide bonds to regulate alternative splicing and pathogenic RNA foci formation.
Muscleblind-like (MBNL) RNA-binding proteins (RBPs) possess modular domains that mediate regulation of alternative splicing and RNA localization. Myotonic Dystrophy Type 1 is a CTG repeat expansion disorder where MBNL is sequestered into intranuclear RNA foci, impairing its function. Previous studies found that MBNL self-associates through its exon 7, but the nature of this interaction is not well understood. We identified a cysteine in MBNL1 exon 7 that enables dimerization through formation of an intermolecular disulfide bond. We likewise demonstrate that MBNL2 dimerizes by forming disulfide bonds between multiple cysteines in its carboxy-terminus. Nucleocytoplasmic fractionation revealed a greater proportion of MBNL1 dimer in the nucleus, suggesting a nuclear function for the MBNL1 dimer. We investigated a connection between MBNL1 dimerization and MBNL1-mediated regulation of alternative splicing. To accomplish this, we mutated the MBNL1 cysteine in question to alanine (C325A) and performed RNAseq. We uncovered novel splicing events sensitive to MBNL1 dimerization. We also found that MBNL1 C325A, when co-expressed with expanded CTG repeats, produces smaller, more numerous foci, suggesting a role for the MBNL1 dimer in maintaining foci integrity. These results provide insight into biological and pathological mechanisms of MBNL1 dimerization and suggest other RBPs might similarly dimerize to regulate function.
gene therapies
2026-08-21 | CRISPR/dCas9-mediated tuning of DMPK transcription reveals a quantitative relationship between toxic repeat RNA expression and MBNL1 activity in myotonic dystrophy.
Myotonic dystrophy type 1 (DM1) is caused by (CUG)n-expanded DMPK transcripts that sequester the splicing factor MBNL1 in the nucleus, resulting in widespread splicing abnormalities. Although significant progress has been made in understanding DM1 pathogenesis, the contribution of DMPK transcript levels to disease severity, and the variability of these levels across cell types, tissues, and patients, remains poorly understood. To investigate this in a quantitative manner, we developed isogenic human immortalized myoblast models with inducible modulation of DMPK RNA levels using CRISPR activation (CRISPRa) and interference (CRISPRi) guided by synthetic sgRNAs. CRISPRa elevated DMPK RNA levels by more than three-fold, intensifying MBNL1-dependent splicing defects. In contrast, CRISPRi reduced DMPK RNA expression by approximately 80%, partially rescuing splicing abnormalities. These changes were validated by visualizing (CUG)n foci using RNA FISH. Lowering DMPK transcript levels increased the availability of free nucleoplasmic MBNL1, whereas upregulation further depleted MBNL1, reinforcing the central role of MBNL1 sequestration in repeat RNA toxicity. Our findings demonstrate that expanded DMPK transcript levels modulate free MBNL1 concentration and alternative splicing in a dose-dependent manner, underscoring the central role of repeat RNA expression in DM1 pathogenesis. These models provide a powerful platform for dissecting variability in DMPK expression and for defining the therapeutic thresholds required for effective DMPK knockdown, thereby offering critical insights for the design and evaluation of DMPK and MBNL1-directed therapeutic strategies.
2026-07-10 | Aberrant neuronal differentiation and splicing defects in Congenital Myotonic Dystrophy (DM1) iPSC models.
Myotonic Dystrophy type 1 (DM1) is an autosomal multisystem disorder manifested due to unstable CTG nucleotide repeat expansion within the 3'-untranslated region of the dystrophia myotonica protein kinase ( DMPK ) gene. Although progress towards understanding of molecular pathogenesis in muscle and heart has been made, the pathways that affect the brain in DM1 is fundamentally unknown. In addition, the congenital DM1 manifest even more complicated brain abnormalities. Despite the wealth of existing cellular and animal models, iPSCs based studies are being fostered as they replicate the human model more closely to the disease. In view of this context, we set out to characterize the differentiation potential of congenital DM1 patient derived iPSC lines towards neuronal cells. Using neurogenin2 (NGN2) induced direct reprogramming of iPSCs into neurons and chemically defined media-induced neural induction protocol, we find that congenital DM1 mutant iPSC derived neurons exhibited precocious differentiation, as evidenced by their expression of pan-neuronal markers TUJ1 and Map2, along with increased processes extension and neurite length. Moreover, unbiased RNA sequencing analyses and qPCR validation revealed precocious and enhanced expression of several neurogenic transcription factors including, Ascl1, NeuroG2, and NeuroD1. Furthermore, immunofluorescence imaging of MBNL1 and MBNL2, RNA-splicing factors, displayed enhanced nuclear aggregations, a hallmark of the DM1 disease, in the mutant lines. Moreover, investigation of RNA splicing events identified mis-splicing in many important genes/transcripts including RMST, ANK3 and MBD1 during the neural conversion of congenital DM1 lines. These studies reveal novel paradigms that may contribute to neurological pathogenesis in CDM1 patients. These studies also provide a strong foundation for future mechanistic investigation aimed at understanding CDM1 pathology and may open new avenues for the development of gene therapy approaches for individuals with DM1.
2026-07-09 | Elimination of myotonia improves myopathy in a muscleblind-like knockout model of myotonic dystrophy.
A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1.
2026-06-25 | Generation of isogenic rescue iPSC lines by targeted CTG-repeat excision for myotonic dystrophy type 1.
An expanded CTG repeat in the Dystrophia Myotonica Protein Kinase (DMPK) gene is associated with myotonic dystrophy type 1 (DM1), an autosomal dominant neuromuscular disorder characterised by progressive muscle weakness, myotonia, cognitive decline, and a variety of other manifestations. Here, we report the generation of isogenic induced pluripotent stem cell (iPSC) lines, derived from patient DM1 iPSC lines carrying varying expanded (CTG)n repeats in DMPK. These gene-edited isogenic iPSC lines, in which the pathogenic repeat has been excised, serve as a reference for assessing DM1-associated phenotypes in relevant differentiated cell types, such as muscle progenitor cells and neurons.
2026-04-18 | Therapeutic Strategies Targeting the Molecular Pathogenesis of Myotonic Dystrophy Type 1: Current Status and Future Directions.
Myotonic dystrophy type 1 is the most prevalent adult-onset muscular dystrophy and is characterized by progressive muscle weakness, myotonia, cardiac conduction defects, endocrine dysfunction, and central nervous system involvement. Myotonic dystrophy type 1 is caused by an unstable CTG repeat expansion in the 3' untranslated region of the DMPK gene, which produces toxic CUG-expanded transcripts that sequester RNA-binding proteins such as Muscleblind-like, induce widespread alternative splicing defects, and drive an RNA gain-of-function mechanism rather than simple DMPK haploinsufficiency. Despite major advances in understanding the molecular pathogenesis of myotonic dystrophy type 1, there is still no approved cure or disease-modifying therapy. This review summarizes the molecular basis of myotonic dystrophy type 1 and provides an in-depth overview of emerging therapeutic strategies that directly target the underlying pathogenic cascade at the DNA and RNA levels. Gene therapy-based approaches, including CRISPR-mediated genome editing, aim to reduce or eliminate the expanded CTG repeats or expanded DMPK allele and its toxic transcripts. In parallel, a broad spectrum of RNA-directed interventions is being developed, encompassing antisense oligonucleotides, antibody-penetrating and cell-penetrating peptide-conjugated antisense oligonucleotides to enhance skeletal and cardiac muscle delivery, small interfering RNAs, and microRNA-based tools such as antagomiRs. Additional strategies exploit engineered RNA-binding proteins and peptide decoys to disrupt toxic ribonuclear aggregates, polyadenylation signal-driven premature transcriptional termination to selectively silence mutant DMPK, and small molecules that modulate RNA metabolism, dissolve CUG RNA foci, or correct downstream mis-splicing. By integrating data from preclinical models and ongoing clinical trials, including recent advances with muscle‑targeted antisense oligonucleotide conjugates and gene therapy, this review outlines the current status, strengths, and limitations of these mechanism-based therapies for myotonic dystrophy type 1. The discussion highlights key translational challenges such as efficient delivery to skeletal muscle, the heart, and brain, long-term safety, and robust pharmacodynamic biomarkers as well as opportunities for combination and next-generation approaches aimed at converting molecular correction into durable clinical benefit for patients with myotonic dystrophy type 1.
other
2026-03-13 | Delpacibart etedesiran improves the molecular pathology of myotonic dystrophy type 1 in the phase 1/2 MARINA study.
Myotonic dystrophy type 1 (DM1) is a rare, autosomal dominant, progressive neuromuscular disease caused by the expansion of CTG repeats in the DM1 protein kinase (DMPK) gene. Expanded CUG repeats in the mutant DMPK transcript bind and sequester splicing factors, especially in the muscleblind-like (MBNL) family, leading to misregulated alternative splicing of mRNA, which is the main driver of DM1 pathology. We designed an antibody-oligonucleotide conjugate (AOC), delpacibart etedesiran (del-desiran), to deliver a DMPK-targeting small interfering RNA to muscle via transferrin receptor 1-mediated cell internalization. Del-desiran reduced mutDMPK mRNA expression, increased estimated levels of functional MBNL, and corrected disease-associated mis-splicing in a dose-dependent manner. The extent of increase in functional MBNL was associated with consistent trends toward muscle function improvement, confirming del-desiran's mechanism of action and supporting its development as a treatment for DM1. The translation of its pharmacodynamic activity from preclinical models (patient-derived myotubes and Macaca fascicularis [cynomolgus monkeys]) to patients with DM1 demonstrates del-desiran's consistency across species and reveals the potential broad utility of the AOC platform in further neuromuscular diseases.
2026-03-02 | The Usage and Limitations of Gene Therapy Versus Stem Cell Therapy for Myotonic Dystrophy Type 1 (DM1): Special Focus on Immune Response
Muscular dystrophies include myotonic dystrophy (MD). Although there is no cure for this disorder, many treatments can manage symptoms and reduce disease development. Standard pharmacological treatments and rehabilitation methods have largely failed, prompting researchers to investigate stem cell and gene therapy options. This review will discuss gene therapy and stem cell therapy as adjuvant therapies for MD, including their benefits, drawbacks, and timeline for implementation. We searched PubMed, Scopus, Web of Science (WOS), Cochrane Library, and Embase from 1980 to 2024 for preclinical and clinical gene therapy papers for MD using keywords such as "myotonic dystrophy" and "gene therapy." A search for "myotonic dystrophy" and "Stem Cell" yielded studies on stem cell treatment for MD. The initial search found 50 gene therapy and 38 stem cell research articles. Following our exclusion and filtering criteria, we deleted 31 articles on gene therapy and 23 articles on stem cells. We found 19 gene therapy publications and 15 stem cell-based publications. Antisense oligonucleotides (ASO), CRISPR technology, and AAV vectors have become the most popular methods. Induced pluripotent stem cells (iPSCs) and muscle-derived progenitor cells (MuSCs) were important cellular sources for investigation or application. Most research focuses on myotonic dystrophy type I (DM1). It is widely established that AAV vector-induced immune responses can affect the safety and efficacy of genetic therapy. Specific stem cells may also modulate MD patients' immunological responses, improving prognosis. Using cytokines and monoclonal antibodies as adjuvants to treat this complex illness is becoming more common.
2024-11-18 | in vivo-like Scaffold-free 3D in vitro Models of Muscular Dystrophies: The Case for Anchored Cell Sheet Engineering in Personalized Medicine
Abstract Progress in understanding the underlying mechanisms of muscle dystrophies and finding effective treatments for them has been hindered by the absence of relevant in vitro models for biomedical research. In this study, an entirely scaffold-free cell sheet engineering-based platform is used to make such in vitro models using patient-specific cells. Unlike reductionist bottom-up approaches, this holistic biofabrication method, termed anchored cell sheet engineering, effectively replicated mature cell phenotypes and tissue- and disease-specific ECM deposited by the cells themselves. Robust anchored 3D muscle fibers were developed using primary cells from both healthy individuals and patients with Duchenne dystrophy and Myotonic dystrophy type 1. Through a combination of histology, immunostaining, and proteomics analysis, it was demonstrated that these models formed mature constructs that closely resembled in vivo conditions, outperforming traditional 2D cultures in their translation potential. Models of diseased tissues, analyzed through various analysis, accurately reflected key phenotypic features of the respective diseases. Furthermore, when treated with therapeutically beneficial drugs, the detailed changes in their proteomic profiles were documented. This novel in vitro modeling approach, compared to other 3D techniques that use exogenous scaffolding or bioink, provides a promising platform for advancing the development of muscle dystrophy models, among other conditions.
2024-11-13 | Longitudinal Course of Myotonic Dystrophy Type 1 With Gait Training Using a Hybrid Assistive Limb: A Case Report.
Muscle dystrophy type 1 is the most common form of muscular dystrophy and is characterized by progressive distal dominant muscle weakness, muscle atrophy, and myotonic phenomena. Patients with progressive neuromuscular diseases such as myotonic dystrophy type 1 are prone to muscle weakness, movement disorders, and fatigue due to their underlying disease, which may limit their physical activity and ambulation. Six courses of gait training with a hybrid assistive limb (HAL) were performed in an adult male with myotonic dystrophy type 1 over 4.5 years. The two-minute walking distance and knee joint strength tended to increase, and the Timed Up and Go test time tended to decrease with gait training with HAL before and after each intervention. In the long term, the two-minute walking distance decreased slowly, but the Timed Up and Go and knee joint strength tended to be maintained. Functional ambulation category and activities of daily living levels were also maintained. These results suggest that intermittent gait training may be an effective rehabilitation method for maintaining gait independence and activities of daily living in patients with myotonic dystrophy type 1. The frequency and number of interventions should be considered for further effectiveness.
2024-09-15 | Ameliorated cellular hallmarks of myotonic dystrophy in hybrid myotubes from patient and unaffected donor cells.
Cell-based strategies are being explored as a therapeutic option for muscular dystrophies, using a variety of cell types from different origin and with different characteristics. Primary pericytes are multifunctional cells found in the capillary bed that exhibit stem cell-like and myogenic regenerative properties. This unique combination allows them to be applied systemically, presenting a promising opportunity for body-wide muscle regeneration. We previously reported the successful isolation of ALP+ pericytes from skeletal muscle of patients with myotonic dystrophy type 1 (DM1). These pericytes maintained normal growth parameters and myogenic characteristics in vitro despite the presence of nuclear (CUG)n RNA foci, the cellular hallmark of DM1. Here, we examined the behaviour of DM1 pericytes during myogenic differentiation. DMPK (CTG)n repeat lengths in patient pericytes were assessed using small pool PCR, to be able to relate variation in myogenic properties and disease hallmarks to repeat expansion. Pericytes from unaffected controls and DM1 patients were cultured under differentiating conditions in vitro. In addition, the pericytes were grown in co-cultures with myoblasts to examine their regenerative capacity by forming hybrid myotubes. Finally, the effect of pericyte fusion on DM1 disease hallmarks was investigated. Small pool PCR analysis revealed the presence of somatic mosaicism in pericyte cell pools. Upon differentiation to myotubes, DMPK expression was upregulated, leading to an increase in nuclear foci sequestering MBNL1 protein. Remarkably, despite the manifestation of these disease biomarkers, patient-derived pericytes demonstrated myogenic potential in co-culture experiments comparable to unaffected pericytes and myoblasts. However, only the unaffected pericytes improved the disease hallmarks in hybrid myotubes. From 20% onwards, the fraction of unaffected nuclei in myotubes positively correlated with a reduction of the number of RNA foci and an increase in the amount of free MBNL1. Fusion of only a limited number of unaffected myogenic precursors to DM1 myotubes already ameliorates cellular disease hallmarks, offering promise for the development of cell transplantation strategies to lower disease burden.
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Drug Discovery Landscape
8 orphan drug designations for Myotonic dystrophy, including 1 approved therapy.
8 orphan drug designations for Myotonic dystrophy, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
RNA, [P-deoxy-P-(dimethylamino)](2',3'-dideoxy-2',3'-imino-2',3'-seco)(2'a->5') (C-A-G-C-A-G-C-A-G-C-A-G-C-A-G-C-A-G-C-A-[2'a-[39-[[1-acetyl-L-prolyl-L-lysyl-L-lysyl-L-lysyl-L-arginyl-L-lysyl-L-valyl-2-[2-(2-aminoethoxy)ethoxy]acetyl-N6-(L-phenylalanylglycyl-L-phenylalanylglycyl-L-arginylglycyl-L-arginyl-L-gamma-glutamyl)-L-lysyl]amino]-1- oxo-4,7,10,13,16,19,22,25,28,31,34,37-dodecaoxanonatriacont-1-yl]]G), (8'->1')-lactam | oligonucleotides | EMA | Vertex Pharmaceuticals (Ireland) Limited | |
Phosphorodiamidate morpholino oligonucleotide against the CUG repeat expansion of the DMPK gene mRNA transcript, conjugated to a cell penetrating peptide | oligonucleotides | EMA | — | Yes Pharmaceutical Development Services GmbH |
mexiletine | small molecules | FDA | Lupin Europe GmbH | |
synthetic oligomer of 16 nucleotides | oligonucleotides | FDA | Ionis Pharmaceuticals, Inc. | |
Mexiletine hydrochloride [Namuscla] | small molecules | EMA | Approved | Lupin Europe GmbH |
(6aS)-1,10-dimethoxy-6-methyl-5,6,6a,7-tetrahydro-4H-dibenzo[de,g]quinoline-2,9-diol | small molecules | EMA | — | Valentia BioPharma S.L |
Mexiletine hydrochloride | small molecules | EMA | Agenzia Industrie Difesa-Stabilimento Chimico Farmaceutico Militare | |
mecasermin | proteins | FDA | Insmed, Inc. |
“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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