small molecules

2026-09-08 | Myotonic Muscle Activity Drives a Persistent Pain State Responsive to NaV1.8-directed Analgesics.

Pain is a common and disabling feature of myotonic disorders, yet its biological basis remains poorly understood and no targeted analgesic therapies currently exist. Here, we demonstrate that skeletal muscle hyperexcitability is sufficient to initiate a persistent pain state independent of inflammation, nerve injury, or overt tissue damage. Using complementary pharmacological and genetic models of myotonia resulting from loss of the voltage-gated skeletal muscle chloride channel ClC-1 function, we show that transient and chronic myotonia produce robust mechanical, thermal, and cold hypersensitivity, as well as spontaneous pain-like behavior. Notably, pain-like behaviors induced by transient myotonia persist long after overt motor symptoms have resolved, suggesting that a transient episode of muscle hyperexcitability is sufficient to trigger prolonged alterations in nociceptive processing. Physiological recordings revealed altered excitability of dorsal root ganglion and superficial dorsal horn neurons and enhanced sensory-evoked activity in the parabrachial nucleus, indicating altered nociceptive processing across multiple levels of the pain neuraxis. Transient myotonia increased total sodium current density in sensory neurons, with a shift toward a greater tetrodotoxin-resistant current fraction. Pharmacological inhibition with the NaV1.8-directed analgesic Suzetrigine markedly attenuated pain-like behaviors in both models of myotonia. Together, these findings establish a link between myotonia and persistent alterations in nociceptive processing and identify NaV1.8-directed analgesia as a promising therapeutic strategy for myotonia-associated pain.

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2026-09-06 | Efficacy of sodium channel blockers in treating myotonia is independent of action potential sodium current block.

The prevailing view holds that the therapeutic benefit of sodium channel blockers arises from use-dependent inhibition of the transient sodium current (NaT) that is responsible for action potentials. This assumption underlies decades of drug development but has never been directly tested. Our goal was to test this assumption to guide the development of more effective sodium channel blockers. We used a mouse model of myotonia congenita, an ion channelopathy of skeletal muscle, as a system to study mechanism and efficacy of both use-dependent and closed sodium channel blockers. Intracellular current-clamp recordings were used to assess excitability during trains of stimuli. The contributions of NaT and a small, non-inactivating current (Na persistent or NaP) were directly measured with voltage-clamp recordings. At their effective concentrations none of the sodium channel blockers reduced action potential rate of rise or voltage clamp measures of NaT. In contrast at effective concentrations, all sodium channel blockers studied reduced NaP. A computational model was constructed to test the relative effects of NaT and NaP inhibition on excitability. The model confirmed that NaT block alone could not eliminate myotonia without causing hypoexcitability, whereas partial NaP block was sufficient to abolish pathological discharges while preserving normal firing. These findings redefine the therapeutic mechanism of sodium channel blockade: efficacy does not depend on blocking NaT but correlates with the inhibition of NaP. This shift in perspective reframes strategies for sodium channel drug development and suggests a novel approach to treating myotonia, neuropathic pain, cardiac arrythmia and epilepsy. KEY POINTS: At effective doses that treat hyperexcitability, Na channel blockers have little effect on the sodium current responsible for action potentials. Electrophysiologic recordings and computer simulation suggest that block of a small, persistent, sodium current (NaP) is the mechanism underlying efficacy in treating hyperexcitability. These findings suggest that screens for novel sodium channel blockers focus on block of NaP.

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2026-08-29 | Case Report: Three pathogenic molecular findings in a patient with myotonia congenita, pseudohypoparathyroidism, and a glaucoma-suspect phenotype.

The presence of multiple rare Mendelian disorders in a single patient may mask clinical recognition when phenotypes overlap. We describe a patient with longstanding myotonia congenita due to a CLCN1 variant in whom an incidental discovery of severe hypocalcemia led to the diagnosis of GNAS-related pseudohypoparathyroidism (PHP). Exome reanalysis also identified an incidental homozygous pathogenic CYP1B1 variant associated with autosomal recessive glaucoma. A 23-year-old man born to consanguineous parents was referred for management of chronic myotonia congenita, manifested by delayed motor milestones, frequent falls, contractures, and muscle hypertrophy. Electrophysiological assessment demonstrated myotonic discharges, and whole-exome sequencing (WES) identified a homozygous CLCN1 splice-site variant (NM_000083.3:c.1167-10T>C) known to cause myotonia congenita. During subsequent evaluation, he was found to have severe hypocalcemia, hyperphosphatemia, markedly elevated parathyroid hormone, basal ganglia and dentate calcifications, brachydactyly, subcutaneous calcifications, and mild hypothyroidism, raising suspicion for PHP. Reanalysis of WES data demonstrated a heterozygous frameshift GNAS variant (NM_080425.4:c.2494_2497delCTGA) and a homozygous CYP1B1 variant (NM_000104.4:c.182G>A; p.Gly61Glu) in addition to the CLCN1 defect. Sanger sequencing confirmed all three variants. The CYP1B1 finding prompted glaucoma-specialist evaluation. Visual acuity was 20/22 in the right eye and 20/25 in the left eye; intraocular pressures were 8 and 12 mmHg, respectively. The corneas were clear, cup-to-disc ratios were 0.4 and 0.5, and average retinal nerve fiber layer thicknesses were 74 and 75 µm. No definite glaucomatous damage was identified, and the patient was classified as a glaucoma suspect. After treatment with calcium, calcitriol, and ergocalciferol, serum calcium improved, parathyroid hormone levels declined, creatine kinase normalized, and the patient reported improved muscle stiffness and function. This case demonstrates two clinically expressed Mendelian disorders together with a third actionable molecular finding. It highlights the importance of careful phenotyping, molecular testing, and cautious genotype-phenotype interpretation, particularly in consanguineous populations.

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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.

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2026-08-12 | Schwartz-Jampel Syndrome: A Case Report with Clinical and Phenotypic Insights

Schwartz-Jampel Syndrome (SJS) is a rare autosomal recessive disorder characterised by myotonia, craniofacial dysmorphism and skeletal dysplasia, resulting from pathogenic variants in Heparan Sulfate Proteoglycan 2 (HSPG2). Pathogenic variants disrupt perlecan function, resulting in abnormal cartilage development and impaired neuromuscular transmission. A three-year and fivemonth-old male presented with blepharophimosis, generalised muscle stiffness, delayed motor milestones and gait abnormality. Electromyography demonstrated continuous spontaneous myotonic discharges. Radiographs revealed metaphyseal dysplasia with epiphyseal abnormalities. Molecular testing identified three heterozygous HSPG2 variants with parental carrier status, consistent with compound heterozygosity. Carbamazepine and structured rehabilitation were administered. Follow-up demonstrated reduction in myotonia, improved gait parameters and decreased fall frequency. In early-onset myotonic disorders, SJS should be considered with characteristic craniofacial and skeletal features. Symptomatic treatment with sodium-channel–blocking agents and multidisciplinary rehabilitation may confer functional benefit.

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proteins

2026-04-20 | 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.

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2026-03-26 | 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.

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2025-12-31 | Genetically Confirmed Schwartz–Jampel Syndrome: An Ultra-Rare Case of Congenital Myotonia with Osteochondrodysplasia from India

Background: Schwartz–Jampel syndrome is a rare autosomal recessive disorder caused by mutations in the HSPG2 gene, leading to perlecan deficiency. Perlecan is a heparan sulfate proteoglycan critical for cartilage integrity, basement membrane stability, and neuromuscular transmission. The disorder manifests with skeletal dysplasia and persistent myotonia, while cognition and lifespan are usually preserved. Only about 150 cases have been reported worldwide. We report a four year old child with severe osteochondrodysplasia and generalized myotonia, highlighting the therapeutic benefit of botulinum toxin A in managing both blepharospasm and perioral myotonia. The Case: A male neonate, born full term to consanguineous parents, was referred on day one of life with suspected skeletal dysplasia. Birth weight was 3.0 kg (−0 to +1 SD), with macrocephaly (>+2 SD) and short length (<−3 SD). Dysmorphic features included a narrow thorax, bent femora and tibiae, retrognathia, long philtrum, and ichthyosis. Infantogram revealed rhizomesomelia with irregular metaphyses of long bones. At four years, he presented with gross motor delay due to sustained skeletal muscle contractions, failure to thrive, and gait difficulty. Anthropometry remained <−3 SD for height, weight, and head circumference. Examination showed generalized myotonia of facial and skeletal muscles, pursed lips, micrognathia, thoracic kyphosis, hip abduction deformities, and hypertrophied muscles. Neurological assessment revealed hypertonia with areflexia, while speech and cognition were preserved. The differential diagnosis includes muscular dystrophies, skeletal dysplasias, myotonic disorders, congenital myopathies, and cramp–stiffness syndromes such as stiff person syndrome and Isaac’s syndrome. However, the coexistence of osteochondrodysplasia with persistent myotonia, supported by whole exome sequencing which revealed a homozygous likely pathogenic variant in the HSPG2 gene (c.5014+2T>C), confirmed the diagnosis. Parental carrier testing showed that both parents were heterozygous carriers of the mutation. Management included carbamazepine and regular physiotherapy, which provided partial benefit. To address disabling blepharospasm and perioral myotonia that impaired feeding, botulinum toxin A injections were administered to the orbicularis oculi and orbicularis oris. This improved both vision and feeding ability, demonstrating an effective extension of botulinum toxin use in this condition. Parents were counseled regarding malignant hyperthermia risk with anesthesia and advised genetic counseling for future pregnancies. Conclusion: Schwartz–Jampel syndrome should be suspected when skeletal dysplasia coexists with generalized myotonia, particularly in children of consanguineous unions. Supportive management includes physiotherapy and anticonvulsants, and botulinum toxin A, though primarily used for blepharospasm, can also enhance feeding through perioral muscle relaxation. Prognosis is generally favorable, as symptoms stabilize after adolescence and cognition remains intact. However, morbidity arises from progressive contractures and skeletal dysplasia, speech and feeding difficulties from facial and oropharyngeal myotonia, restrictive lung disease due to a narrow thorax, and the psychosocial burden of visible deformities with reduced mobility. Early recognition, multidisciplinary care, and family counseling, including genetic counseling for future pregnancies, are essential to optimize outcomes in this rare disorder.

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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.

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2025-10-28 | Distinct Cellular Effects of Myotonic Dystrophy type 2 RAN Tetrapeptides in Drosophila melanogaster

ABSTRACT 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 may produce two tetrapeptide repeat proteins (TPRs), poly-QAGR and poly-PACL, whose roles in DM2 pathogenesis remain poorly understood. To investigate their individual contributions, we expressed codon-optimized QAGR and PACL peptides with ATG start codon in Drosophila melanogaster . Expression of QAGR and PACL TPRs significantly compromised fly viability and lifespan, induces eye degeneration and locomotor defects. We found that QAGR accumulated in the nucleolus, disrupted nucleolar integrity, and compromised rRNA processing. Moreover, QAGR expression interfered with autophagy, leading to the accumulation of Atg8a– and Ref(2)P-positive aggregates. Genetic interaction studies showed that overexpression of Atg8a or Ref(2)P mitigated QAGR-induced eye-toxicity, while knockdown of autophagy genes exacerbated it. Conversely, PACL repeats promoted stress granule formation, as indicated by their colocalization with TIAR in human cells and their epistatic interaction with the Drosophila orthologue Rox8. Notably, cytoplasmic PACL aggregates were observed in myoblasts of DM2 patient. Together these findings demonstrate that QAGR and PACL peptides exert distinct toxic effects, impairing nucleolar function and autophagy, or altering stress granule dynamics, respectively. Both mechanisms likely converge to drive DM2 pathogenesis and represent promising therapeutic targets.

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gene therapies

2026-08-22 | Myotonic dystrophy type 1 - updates on mechanisms of multisystemic manifestations, genetically targeted therapeutics, and preparing for a postapproval world.

Myotonic dystrophy type (DM1) is the most prevalent muscular dystrophy and manifests throughout the lifespan with signs and symptoms in all major organ systems. There are significant updates on therapeutic development and trials focused on muscle disease in DM1, as well as updates on the mechanism and progression of disease in nonmuscle tissues, changes or updates on clinical management, and the societal burden associated with a varied and prevalent disorder. Evidence of improvement with strength and myotonia with genetically targeted treatments in early phase trials. Preparation for natural history studies to evaluate the impact of therapeutics on the heart and central nervous system (CNS), and expansion to early onset forms of DM1. Improvements in our understanding of mechanisms of CNS, cardiac, gastrointestinal, and liver manifestations. Evolving approaches to cardiac monitoring and respiratory care. DM1 is genetically more common than recognized clinically, and how this may affect societal disease burden. This review highlights genetically targeted therapeutics showing impact for muscle manifestations of DM1, ongoing efforts now shifting to expand to other target tissues and the younger population, and, in preparation for a clinically available medicine, our understanding of societal burden and population genetics of DM1.

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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.

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2026-07-09 | Tissue-specific CTG•CAG expansion rate and disease severity are modified by DNA repair genes expression levels in myotonic dystrophy type 1 patients.

Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder caused by the expansion of an unstable CTG•CAG repeat in the DMPK gene. This study examined whether differential expression of DNA repair genes in three different tissues from the same DM1 patient contributed to tissue-specific somatic instability of the repeat tract. RNA-Seq was used to quantify expression levels of eight DNA repair genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS2, LIG1, and FAN1). Results indicate that the expression levels varied significantly across tissues, with no inter-tissue correlations, suggesting independent regulation and patient-specific differences. Somatic expansion of the repeat tract in blood and muscle was effectively predicted by a complex ePALxAge interaction, while in muscle it was further influenced by MSH3 and PMS2 gene expression, confirming their role as tissue-specific genetic modifiers in DM1. Although only marginally significant, muscle expression of PMS2 and FAN1 appeared to affect age-at-onset: higher FAN1 expression was associated with reduced somatic expansion and later onset. Our findings also suggest a complex competitive balance between promoters and stabilizers of repeat instability, shaping muscle expansion dynamics and potentially modifying clinical onset. Overall, these results indicate that certain DNA repair genes exert stronger, tissue-dependent effects on somatic instability. We confirm that MSH3, PMS2, and FAN1 act as key modifiers not only of somatic expansion, especially in skeletal muscle, but also of DM1 severity. Although RT-qPCR data might be required to validate some of these results, these genes therefore represent promising therapeutic targets for modulating disease progression.

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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.

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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.

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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.

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2026-06-24 | Bottlebrush polymer conjugates for enhanced antisense oligonucleotide therapy in myotonic dystrophy type 1.

Oligonucleotides are a promising class of genetic medicine for myotonic dystrophy type 1 (DM1), the most common adult-onset muscular dystrophy. However, poor muscle distribution of nucleic acid drugs following systemic administration has hindered drug development, and no curative treatment currently exists. DM1 pathology requires drug localization to the nucleus, where pathogenic mutant RNA is sequestered, posing additional challenges after cellular internalization regarding endosomal escape and nuclear uptake. Here, we show that a locked nucleic acid oligonucleotide targeting mutant CUG repeat RNA tracts, conjugated to a bottlebrush polymer, exhibits improved muscle distribution and potent correction of DM1-associated splicing dysregulation in a DM1 mouse model. Significant improvements in myotonia, body weight, and grip strength were observed. The conjugate was well tolerated following 12 weeks of weekly intravenous administration. These findings suggest that bottlebrush polymer conjugates may overcome key limitations of conventional oligonucleotide therapeutics for neuromuscular conditions, with potential to become a potent and cost-effective DM1 therapy.

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2026-06-16 | Enhancing Antisense Oligonucleotide Activity in Myotonic Dystrophy Type 1 by Genetic and Chemical Modulation

Myotonic dystrophy type 1 (DM1) is an RNA gain-of-function disorder caused by expanded CT repeats in the DMPK gene.Mutant DMPK transcripts accumulate as nuclear RNA foci and sequester Muscleblind-like (MBNL) proteins, leading towidespread spliceopathy and multisystemic disease manifestations. In addition to toxic RNA-mediated MBNLsequestration, dysregulation of specific microNAs further contributes to DM1 pathogenesis. In particular, miR-23bnegatively regulates MBNL1 expression, while anti-miR-23b therapeutic strategies have demonstrated restoration of MBNLactivity and improvement of DM1-associated phenotypes in preclinical models. Antisense oligonucleotide (ASO)-basedtherapeutic strategies are currently under development for DM1, including RNase H-mediated degradation of toxic DMPKtranscripts, steric-blocking approaches and modulation of pathogenic RNA-protein interactions. Multiple ASO-basedtherapeutic strategies targeting toxic DMPK RNA are currently advancing through preclinical and clinical development (seePoster 84: "Therapeutic Innovation, Clinical Trial Acceleration, and Lifestyle Interventions in Myotonic Dystrophy Type 1: ASystematic Review"). Despite promising therapeutic potential, productive intracellular delivery remains a major limitationfor oligonucleotide therapeutics. Following endocytic uptake, most ASOs remain trapped within endosomalcompartments, severely limiting productive nuclear delivery and therapeutic efficacy. Current approaches to enhanceendosomal escape include membrane-disrupting arents. lipid-based carriers. cell-penetrating peptides and modulation ofintracellular trafficking pathways?

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2026-06-06 | Antisense-mediated gene therapy targeting DMPK restores cardiac ion channel function and electrical stability in myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is characterized by toxic RNA gain of function leading to cardiac conduction defects and life-threatening arrhythmias. Current therapeutic options remain limited. We evaluated the molecular and electrophysiological efficacy of IONIS-486178, an antisense oligonucleotide (ASO) targeting mutant DMPK transcripts in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) generated from a patient with DM1. DM1 hiPSC-CMs were treated with IONIS-486178 for 24 hours. Efficacy was assessed using reverse transcription quantitative polymerase chain reaction for DMPK knockdown and splicing analysis, fluorescence in situ hybridization for nuclear foci quantification, western blot for ion channel protein expression, and whole-cell patch clamp for ionic currents and action potential characterization. Treatment of hiPSC-CMs with IONIS-486178 (5 μmol/L) achieved ∼90% DMPK knockdown, reduced toxic nuclear foci, and corrected SCN5A mis-splicing toward the adult isoform. Functionally, IONIS-486178 fully restored all ionic currents (sodium, L-type calcium, and potassium currents) reduced in DM1 hiPSC-CMs. This electrophysiological rescue correlated with re-expression of the corresponding ion channel proteins. The treatment also normalized action potential kinetics and durations and significantly reduced the incidence of arrhythmogenic events. ASO-mediated suppression of DMPK is sufficient to reverse core electrophysiological defects and reduce arrhythmogenic events in a human cellular model of DM1. These findings validate the biological rationale of targeting DMPK to prevent DM1-associated cardiac complications, supporting the continued development of next-generation ASO delivery platforms.

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2026-05-29 | The myotonic dystrophy type 1 drug development pipeline: 2026 Edition.

Over the past few years, therapeutic development for myotonic dystrophy type 1 has accelerated markedly, with ongoing clinical trials nearly doubling and several candidates advancing to late-stage evaluation. Approaches have diversified, including small molecules, antibody-oligonucleotide conjugates, enhanced-delivery antisense platforms, gene therapy and miRNA-targeting strategies. Several nucleic-acid-based therapies demonstrate robust target engagement and clinically meaningful signals, positioning this modality as highly promising for disease modification. Parallel preclinical research has expanded the range of mechanisms under investigation, while structured exercise and rehabilitation continue to emerge as complementary nonpharmacological interventions. Together, these developments illustrate a therapeutic landscape entering an unprecedented phase of maturity, with multiple avenues progressing simultaneously toward potential clinical translation.

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other

2025-09-24 | Electrocardiogram vs Electrophysiological Study and Major Conduction Delays in Myotonic Dystrophy Type 1.

For the prevention of sudden cardiac death in myotonic dystrophy type 1 (dystrophia myotonica; DM1), professional practice guidelines recommend pacemaker implantation in asymptomatic patients with a PR interval greater than or equal to 240 milliseconds and/or QRS duration greater than or equal to 120 milliseconds on electrocardiogram (ECG), or a His-ventricular (HV) interval greater than or equal to 70 milliseconds during electrophysiological study (EPS), as class IIa indications. To determine which of these strategies-ECG or EPS based-is more effective in predicting major bradyarrhythmic events (MBAEs). This was a cohort analysis of retrospectively collected longitudinal data from the DM1 Heart Registry. The setting included cardiology and neurology departments of 6 French university hospitals. Study participants were selected from individuals enrolled in the DM1 Heart Registry between 2000 and 2020. The DM1 Heart Registry includes adults with genetically confirmed DM1. Included patients had a history of first EPS after 1999 and no personal history of advanced atrioventricular block or sustained ventricular tachycardia. Study data were analyzed from January to July 2025. ECG- and EPS-based strategies. The primary outcome was MBAEs, defined as sudden cardiac death, resuscitated cardiac arrest, or second-degree type II or complete atrioventricular block. Of 1778 adults with genetically confirmed DM1 enrolled in the DM1 Heart Registry, a total of 706 patients (mean [SD] age, 42 [13] years; 359 male [51%]) were included in this study. At baseline, 273 patients (38%) had an HV interval greater than or equal to 70 milliseconds, and 232 (32%) met ECG criteria. Over a median (IQR) follow-up of 5.9 (2.3-9.7) years, 99 patients (14%) experienced an MBAE. In multivariable Cox and joint models incorporating baseline and time-varying values of PR and QRS durations, the HV interval was the only variable significantly associated with the incidence of MBAEs (hazard ratio [HR], 1.77; 95% CI, 1.46-2.16; P < .001 and HR, 1.78; 95% CI, 1.40-2.22; P = .001, respectively). Compared with ECG-based criteria, the EPS criterion proved to be a more reliable (HR, 2.89; 95% CI, 1.92-4.34 vs HR, 1.95; 95% CI, 1.31-2.89) and more sensitive (performance index [SE], 68.35% [6.24%] vs 34.76% [6.47%]) predictor of MBAE and accurately reclassified 28.8% of patients with an MBAE. Lowering the threshold to HV greater than or equal to 65 milliseconds further improved sensitivity (performance index [SE], 90.18% [3.85%]) and net reclassification improvement (33.7%; 95% CI, 19.6%-48.2%) for MBAE prediction. In this cohort of patients with DM1, the HV interval outperformed ECG criteria in predicting MBAEs. An HV threshold greater than or equal to 65 milliseconds may enhance risk stratification for prophylactic pacing.

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2025-09-23 | Effectiveness of the capability approach in rehabilitation for persons with neuromuscular diseases: A controlled before-after study.

Rehabilitation of persons with neuromuscular diseases (NMD) requires a personalised approach that focuses on achieving and maintaining a level of functioning that enables them to be in a state of well-being. The capability approach states that well-being should be understood in terms of capabilities, which are the opportunities that people have to be and do things they have reason to value. The aim of this study is to investigate whether providing care inspired by the capability approach (capability care) has an effect on the well-being of persons with NMD. In the Rehabilitation and Capability care for persons with NeuroMuscular Diseases (ReCap-NMD) study, 64 adults with facioscapulohumeral muscular dystrophy or myotonic dystrophy type 1 were included in two groups, using a before-after controlled design with 6 months between the measurement moments. The first group received rehabilitation as usual, the second received capability care. This article reports on the primary outcome measure, the Canadian Occupational Performance Measure (COPM) and secondary quantitative outcome measures (questionnaires on participation, capability well-being and health-related quality of life). There was no difference between capability care and usual care on the COPM and the secondary outcome measures. There was a similar improvement for both capability care and usual rehabilitation on the COPM at 6-month follow-up. This means that the effect of capability care is similar to usual rehabilitation. This is the first study that explicitly developed, implemented and evaluated a clinical healthcare intervention inspired by the capability approach. We found no difference on the COPM between persons with NMD receiving capability care compared to usual rehabilitation. There is a need for further research on the clinical relevance and added value of the capability approach for rehabilitation and other fields in healthcare. Trialregister.nl NL8946.

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2025-02-28 | Use of HSALR female mice as a model for the study of myotonic dystrophy type I.

HSALR mice are the most broadly used animal model for studying myotonic dystrophy type I (DM1). However, so far, HSALR preclinical studies have often excluded female mice or failed to document the biological sex of the animals. This leaves an unwanted knowledge gap concerning the differential development of DM1 in males and females, particularly considering that the disease has a different clinical presentation in men and women. Here we compared typical functional measurements, histological features, molecular phenotypes and biochemical plasma profiles in the muscles of male and female HSALR mice in search of any significant between-sex differences that could justify this exclusion of female mice in HSALR studies and, critically, in candidate therapy assays performed with this model. We found no fundamental differences between HSALR males and females during disease development. Both sexes presented comparable functional and tissue phenotypes, with similar molecular muscle profiles. The only sex differences and significant interactions observed were in plasma biochemical parameters, which are also intrinsically variable in patients with DM1. In addition, we tested the influence of age on these measurements. We therefore suggest including female HSALR mice in regular DM1 studies, and recommend documenting the sex of animals, especially in studies focusing on metabolic alterations. This will allow researchers to detect and report any potential differences between male and female HSALR mice, especially regarding the efficacy of experimental treatments that could be relevant to patients with DM1.

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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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2024-05-24 | Prophylactic immunoglobulin therapy for pediatric congenital myotonic dystrophy.

Congenital Myotonic Dystrophy (CMD) is an autosomal dominant hereditary disease caused by mutations in the dystrophia myotonica protein kinase gene. Patients with CMD often exhibit low immunoglobulin (Ig) G levels. While Ig replacement therapy for low IgG levels has been reported in several adult cases, there have been no reports on pediatric patients. This study presents a first pediatric case where Ig replacement therapy effectively eliminated susceptibility to infections. The CMD patient, a 1-year-old Japanese female with a history of premature birth and necrotizing enterocolitis, developed recurrent severe bacterial infections due to hypogammaglobulinemia. Intravenous immunoglobulin (IVIG) (600 mg/kg/month) was administered but failed to maintain sufficient serum trough IgG levels. The dosage was increased to 2 g/kg/month, and later, the treatment shifted to subcutaneous immunoglobulin (SCIG), resulting in a stable serum trough IgG level above 700 mg/dL for one year. The cause of hypogammaglobulinemia in CMD patients remains unclear, but potential mechanisms, including IgG-mediated hypercatabolism by alterations in the neonatal Fc receptor, have been considered. Genetic testing ruled out common variable immunodeficiency, and other potential causes were excluded. The study suggests that higher doses of IVIG or SCIG can effectively prevent severe infections associated with CMD-induced hypogammaglobulinemia in children. This case report sheds light on the efficacy of immunoglobulin therapy in pediatric congenital myotonic dystrophy (CMD). We anticipate that our findings will have a positive impact on clinical practice by providing insights into the prevention of severe infections associated with CMD-induced hypogammaglobulinemia. This research is of great interest to the readers of the journal as it addresses an unmet need in pediatric CMD management by providing a strategy for successful immunoglobulin therapy for the treatment of pediatric CMD.

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