RARE DISEASE
Steinert myotonic dystrophy
Steinert myotonic dystrophy
Steinert myotonic dystrophy
Synonyms: Myotonic dystrophy type 1, Steinert disease
Synonyms: Myotonic dystrophy type 1, Steinert disease
Synonyms: Myotonic dystrophy type 1, Steinert disease
Drug discovery
12
drugs
With orphan designations
Overview
Steinert myotonic dystrophy (DM1) is an autosomal dominant multisystem disorder caused by a CTG trinucleotide repeat expansion in the DMPK gene. It manifests with progressive muscle weakness, myotonia, cardiac conduction defects, cataracts, endocrine dysfunction, and neuropsychiatric impairments. The most common adult-onset muscular dystrophy, DM1 exhibits anticipation, with congenital forms showing severe neonatal complications. Prevalence ranges from 1/2,300 to 1/8,000, with regional variations like 1/600 in Quebec's founder populations [1][16][19].
Therapies
Categories: rare cardiac diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neurological diseases, rare ophthalmic disorders, rare transplant-related disorders
Research Papers
977 drug discovery papers about Steinert myotonic dystrophy, with 4 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
977 drug discovery papers about Steinert myotonic dystrophy, with 4 first-in-class and 9 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | A mouse model of myotonic dystrophy type 1 exhibits pain-like behavior and peripheral nociceptor hyperexcitability.
Pain is a prevalent and disabling symptom of myotonic dystrophy type 1 (DM1), yet its underlying mechanisms remain poorly understood. Using HSA LR20b transgenic mice, we found multimodal mechanical and thermal hypersensitivity. Whole-cell electrophysiological recordings demonstrated depolarized resting membrane potentials and increased action potential firing selectively in small- and medium-diameter dorsal root ganglion neurons. These findings identify peripheral nociceptor sensitization as a potential mechanism contributing to pain in DM1.
2026-09-05 | Treatment updates in myotonic disorders.
Myotonia is delayed muscle relaxation after forceful contraction. It is due to hyperexcitability of the skeletal muscle membrane. It can arise from primary skeletal muscle ion channel dysfunction, involving chloride or sodium channels, but is also a prominent clinical feature in myotonic dystrophies where altered RNA splicing leads to secondary ion channel dysregulation amongst other systemic manifestations. Clinically, myotonia can range from delayed eye opening to a disabling symptom causing impaired mobility, functional difficulty and sometimes pain. It can also be a "hidden disability" with many patients feeling socially embarrassed by "looking healthy", yet being unable to do everyday physical tasks or to do them as effortlessly as their peers. It is a symptom that almost always indicates a genetic diagnosis, although it can occur in acquired conditions, including metabolic and drug-induced causes. To experience myotonia without knowing what it is can be baffling. To receive a genetic diagnosis associated with it can be life changing. Although there is no cure, there are many effective and available symptomatic treatments for myotonia and currently we are in an exciting era of clinical trials for new molecular disease-modifying therapies for myotonic dystrophy type 1. In this review, we consider recent developments in the treatment of myotonic disorders and how they may change clinical practice.
2026-08-21 | Pre-systemic Metabolism and Pharmacokinetic Characterization of Enzymatically Modified Isoquercitrin, a Potential Therapeutic for Myotonic Dystrophy Type 1
Quercetin is a natural flavonoid with therapeutic potential, but its oral bioavailability is limited by poor aqueous solubility and extensive pre-systemic metabolism. Enzymatically modified isoquercitrin (EMIQ) is a soluble glucosylated precursor that releases quercetin upon sequential hydrolysis after oral administration and has emerged as a therapeutic lead for myotonic dystrophy type 1 (DM1). This dissertation tested the hypothesis that EMIQ shields quercetin from pre-systemic intestinal glucuronidation, improving oral bioavailability relative to direct quercetin aglycone ingestion. A sensitive single-quadrupole LC-MS assay for quercetin was developed and partially validated in mouse and human plasma, requiring only 10 µL per sample (LLOQ 70 nM) to enable microsampling. In pooled human intestinal S9 fraction, hydrolytic release of quercetin from EMIQ exceeded its glucuronidation during initial times, and a well-stirred gut model predicted a fraction escaping intestinal metabolism of 88.3% for EMIQ-derived quercetin versus 20.6% for quercetin aglycone. Rat and mouse skeletal muscle exhibited β-glucuronidase activity capable of deconjugating quercetin glucuronides, relevant to DM1 where skeletal muscle is an important target site. In FVB/n mice, oral EMIQ delivered 6.2-fold higher total quercetin exposure than equimolar quercetin. Apparent oral bioavailability was 38.2% for EMIQ versus 6.2% for quercetin, and true bioavailability (Ftrue) for free quercetin was 2.65%, the first such value reported for EMIQ. Chronic 12-week dosing of EMIQ showed no systemic accumulation, while quercetin reached micromolar levels in skeletal muscle. Together with skeletal muscle β-glucuronidase activity, this explains how a low Ftrue could still support therapeutic activity, providing a framework for DM1 and beyond.
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.
proteins
2026-08-01 | P172 - ECE_3990 - JUV-161 reverses skeletal muscle myopathy and functional decline in a translational model of myotonic dystrophy type 1
Abstract Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by toxic CUG repeat expansions in the 3′ untranslated region (UTR) of the DMPK gene, leading to progressive skeletal muscle weakness, myopathy, and functional decline. Despite substantial unmet clinical need, therapeutic development for DM1 has been limited by the lack of preclinical models that faithfully recapitulate the systemic pathology and functional impairments observed in patients. At Juvena Therapeutics, we have developed a biologics-based drug discovery platform focused on identifying stem-cell secreted proteins capable of restoring tissue health. This platform led to the identification of JUV-161, a novel secreted protein engineered to enhance muscle regeneration and functional repair. To enable translational evaluation of JUV-161 in DM1, we developed the panCUG960/+ mouse model, a murine system that integrates key genotypic, phenotypic, and functional hallmarks of human DM1 within a single animal. The panCUG960/+ mouse harbors an expanded CUG repeat in the 3′ UTR of the DMPK gene, resulting in accumulation of nuclear RNA foci and widespread splicing abnormalities. These molecular defects drive canonical DM1-associated histopathologic changes accompanied by progressive functional deficits closely mirroring the clinical trajectory in patients with DM1. Using this translationally relevant model, we evaluated the therapeutic efficacy of JUV-161. PanCUG960/+ mice received daily subcutaneous administration of JUV-161 at a dose of 12 mg/kg for 21 days. Treatment with JUV-161 significantly improved gastrocnemius muscle mass (180 mg vs 160 mg in vehicle, P < .01) and tibialis anterior muscle cross-sectional area (1.92E3 µm² vs 1.82E3 µm², P < .01) in male mice. Furthermore, treated animals demonstrated significant improvement in both specific forelimb grip strength (28.5 mN/g vs 23.2 mN/g in vehicle; P < .01) and all-limb grip strength (66.4 mN/g vs 56.1 mN/g in vehicle; P < .001). In contrast, vehicle-treated mice showed a steady decline in grip strength over the 3-week treatment period, indicating meaningful restoration of functional capacity with JUV-161. JUV-161 treatment also significantly lowered non-fasting blood glucose levels relative to baseline compared with vehicle treatment (−8.74% vs −0.04% in vehicle, P < .05). In conclusion, JUV-161 reverses both structural and functional manifestations of skeletal muscle myopathy in a robust and disease-relevant model of DM1. These findings support JUV-161 as a promising therapeutic candidate for treating DM1 and related muscle-wasting conditions.
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.
2026-04-03 | 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.
2026-01-22 | Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in Caenorhabditis elegans with toxic trinucleotide repeats.
Expansion of nucleotide repeat sequences is linked to a growing number of neuromuscular degenerative disorders. Metabolic changes, including disruptions in mitochondrial function and dynamics, characterize these disorders and are believed to contribute to organismal toxicity. To investigate how toxic RNA repeats affect mitochondria, we used a Caenorhabditis elegans model that expresses expanded CUG repeat RNAs in muscle cells and recapitulates muscle dysfunction. We found that the RNA-binding protein Muscleblind-like 1 (MBL-1) is essential for normal mitochondrial function and regulates organelle morphology. In animals expressing expanded CUG repeats, where MBL-1 function is impaired, we identified two distinct mechanisms of mitochondrial disruption: altered mitochondrial morphology regulated by MBL-1, and oxidative phosphorylation (OxPhos) dysfunction occurring independently of MBL-1. Our data further show that changes in mitochondrial morphology are specifically linked to nuclear MBL-1 dysfunction, which affects cpt-3 expression, a gene encoding carnitine palmitoyltransferase-an enzyme required for fatty acid transport into mitochondria. This mechanism is conserved, with similar disruptions observed in patients with Myotonic Dystrophy type 1. Importantly, our findings indicate that increased organelle fragmentation is not central to cellular pathogenesis. Instead, OxPhos dysfunction appears to be a primary contributor to organismal toxicity.
2025-08-13 | MBNL Depletion Induces Muscle Stem Cell Activation and Myofibre Fusion while Impairing Myonuclear Maturation in Myotonic Dystrophy Type 1
Whether skeletal muscle in myotonic dystrophy type 1 (DM1) maintains its regenerative potential or shows inherent muscle stem cell (MuSC) defects remains unresolved. Here, we examine MuSC function in DM1 by combining an adult-onset Mbnl1/2 knockout mouse model with single-nucleus RNA sequencing (snRNA-seq) of human DM1 muscle biopsies. Loss of Mbnl in mouse myofibres triggers MuSC activation and fusion, resulting in central nuclear accumulation independent of degeneration. Lineage tracing confirms direct MuSC contribution to these nuclei, a process abolished upon MuSC ablation. In human DM1 specimens, we identify activated MuSCs and a myonuclear population with an immature transcriptional signature including expression of MuSC markers, and elevated DMPK levels. These findings imply that MuSCs in DM1 contribute to muscle repair by fusing into myofibres but give rise to immature myonuclei, likely due to toxic RNA effects on transcriptional reprogramming. Our study emphasises a previously overlooked role of MuSCs in DM1 pathology and identifies potential targets to support muscle regeneration.
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.
2026-06-16 | 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.
2026-06-06 | 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.
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.
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.
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.
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.
other
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.
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.
2024-12-24 | In Vivo-Like Scaffold-Free 3D In Vitro Models of Muscular Dystrophies: The Case for Anchored Cell Sheet Engineering in Personalized Medicine.
Progress in understanding the underlying mechanisms of muscular dystrophies is hindered by the lack of pathophysiologically relevant in vitro models. Here, an entirely scaffold-free anchored cell sheet engineering platform is used to create patient-specific three-dimensional (3D) skeletal muscle in vitro models. This approach effectively replicates mature muscle phenotypes and tissue- and disease-specific extracellular matric (ECM). Models were developed using primary cells from healthy individuals and patients with Duchenne Muscular Dystrophy and Myotonic Dystrophy Type 1. Through a combination of quantified histological staining (Hematoxylin & Eosin, Movat's Pentachrome, Masson's Trichrome) and immunostaining (desmin, myosin heavy chain, laminin, and dystrophin), it was demonstrated that the models formed mature constructs closely resembling their respective in vivo conditions. Proteomics analysis revealed that the models exhibited appropriate upregulation and downregulation of disease-relevant pathways. Models of diseased tissues accurately reflected key phenotypic features of the diseases, including alterations in muscle fiber integrity and ECM composition. Upon treatment with therapeutically beneficial drugs, significant changes in their proteomic profiles were documented, highlighting the models' potential for drug screening. This novel in vitro modeling approach, unlike other 3D techniques that rely on exogenous biomaterials that interfere with natural cellular behaviors, provides a promising platform for studying muscular dystrophies.
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.
2024-06-04 | Imperfect hairpins formed by CTG trinucleotide repeats are heteroduplex DNA molecules in living cells
Abstract There are over fifty microsatellite expansion disorders, often neurodegenerative pathologies, due to large expansions of tandem repeat sequences. These microsatellites vary in motif composition, size and copy number in the genome. The ability of these repeats to form secondary structures in vitro is strongly suspected to trigger the expansion process and therefore, the pathology. However, there is no formal proof that similar structures are formed in vivo , in living and replicating cells. We are focused on the CTG trinucleotide repeat whose expansion is responsible for myotonic dystrophy type 1 (DM1 or Steinert disease), affecting 1 in 8,000 people worldwide. A series of llama nanobodies (V H H) were selected to bind to the secondary structure formed by a synthetic imperfect CTG hairpin. Yeast one-hybrid was used to identify V H H that were able to activate a reporter gene in vivo . One of them was shown to be very specific since it binds a CTG hairpin but not a CAG hairpin or a GC-rich sequence. This nanobody also bind to long CTG trinucleotide repeats carried by plasmidic or genomic DNAs, proportionally to the number of repeats, suggesting that longer repeats tend to form more frequently imperfect hairpins. Finally, the V H H was bound to a protein G column and used to selectively enrich structure-containing DNA molecules, that were further observed by electron microscopy. They exhibit different kinds of structures in which only one strand is folded into an imperfect hairpin. Our results unambiguously show that alternative DNA structures are transiently formed by CTG trinucleotide repeats in living bacterial and yeast cells and suggest that imperfect CTG hairpins mainly exist in vivo mainly as heteroduplex DNA molecules.
small molecules
2026-09-24 | A mouse model of myotonic dystrophy type 1 exhibits pain-like behavior and peripheral nociceptor hyperexcitability.
Pain is a prevalent and disabling symptom of myotonic dystrophy type 1 (DM1), yet its underlying mechanisms remain poorly understood. Using HSA LR20b transgenic mice, we found multimodal mechanical and thermal hypersensitivity. Whole-cell electrophysiological recordings demonstrated depolarized resting membrane potentials and increased action potential firing selectively in small- and medium-diameter dorsal root ganglion neurons. These findings identify peripheral nociceptor sensitization as a potential mechanism contributing to pain in DM1.
2026-09-05 | Treatment updates in myotonic disorders.
Myotonia is delayed muscle relaxation after forceful contraction. It is due to hyperexcitability of the skeletal muscle membrane. It can arise from primary skeletal muscle ion channel dysfunction, involving chloride or sodium channels, but is also a prominent clinical feature in myotonic dystrophies where altered RNA splicing leads to secondary ion channel dysregulation amongst other systemic manifestations. Clinically, myotonia can range from delayed eye opening to a disabling symptom causing impaired mobility, functional difficulty and sometimes pain. It can also be a "hidden disability" with many patients feeling socially embarrassed by "looking healthy", yet being unable to do everyday physical tasks or to do them as effortlessly as their peers. It is a symptom that almost always indicates a genetic diagnosis, although it can occur in acquired conditions, including metabolic and drug-induced causes. To experience myotonia without knowing what it is can be baffling. To receive a genetic diagnosis associated with it can be life changing. Although there is no cure, there are many effective and available symptomatic treatments for myotonia and currently we are in an exciting era of clinical trials for new molecular disease-modifying therapies for myotonic dystrophy type 1. In this review, we consider recent developments in the treatment of myotonic disorders and how they may change clinical practice.
2026-08-21 | Pre-systemic Metabolism and Pharmacokinetic Characterization of Enzymatically Modified Isoquercitrin, a Potential Therapeutic for Myotonic Dystrophy Type 1
Quercetin is a natural flavonoid with therapeutic potential, but its oral bioavailability is limited by poor aqueous solubility and extensive pre-systemic metabolism. Enzymatically modified isoquercitrin (EMIQ) is a soluble glucosylated precursor that releases quercetin upon sequential hydrolysis after oral administration and has emerged as a therapeutic lead for myotonic dystrophy type 1 (DM1). This dissertation tested the hypothesis that EMIQ shields quercetin from pre-systemic intestinal glucuronidation, improving oral bioavailability relative to direct quercetin aglycone ingestion. A sensitive single-quadrupole LC-MS assay for quercetin was developed and partially validated in mouse and human plasma, requiring only 10 µL per sample (LLOQ 70 nM) to enable microsampling. In pooled human intestinal S9 fraction, hydrolytic release of quercetin from EMIQ exceeded its glucuronidation during initial times, and a well-stirred gut model predicted a fraction escaping intestinal metabolism of 88.3% for EMIQ-derived quercetin versus 20.6% for quercetin aglycone. Rat and mouse skeletal muscle exhibited β-glucuronidase activity capable of deconjugating quercetin glucuronides, relevant to DM1 where skeletal muscle is an important target site. In FVB/n mice, oral EMIQ delivered 6.2-fold higher total quercetin exposure than equimolar quercetin. Apparent oral bioavailability was 38.2% for EMIQ versus 6.2% for quercetin, and true bioavailability (Ftrue) for free quercetin was 2.65%, the first such value reported for EMIQ. Chronic 12-week dosing of EMIQ showed no systemic accumulation, while quercetin reached micromolar levels in skeletal muscle. Together with skeletal muscle β-glucuronidase activity, this explains how a low Ftrue could still support therapeutic activity, providing a framework for DM1 and beyond.
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.
proteins
2026-08-01 | P172 - ECE_3990 - JUV-161 reverses skeletal muscle myopathy and functional decline in a translational model of myotonic dystrophy type 1
Abstract Myotonic dystrophy type 1 (DM1) is a multisystemic neuromuscular disorder caused by toxic CUG repeat expansions in the 3′ untranslated region (UTR) of the DMPK gene, leading to progressive skeletal muscle weakness, myopathy, and functional decline. Despite substantial unmet clinical need, therapeutic development for DM1 has been limited by the lack of preclinical models that faithfully recapitulate the systemic pathology and functional impairments observed in patients. At Juvena Therapeutics, we have developed a biologics-based drug discovery platform focused on identifying stem-cell secreted proteins capable of restoring tissue health. This platform led to the identification of JUV-161, a novel secreted protein engineered to enhance muscle regeneration and functional repair. To enable translational evaluation of JUV-161 in DM1, we developed the panCUG960/+ mouse model, a murine system that integrates key genotypic, phenotypic, and functional hallmarks of human DM1 within a single animal. The panCUG960/+ mouse harbors an expanded CUG repeat in the 3′ UTR of the DMPK gene, resulting in accumulation of nuclear RNA foci and widespread splicing abnormalities. These molecular defects drive canonical DM1-associated histopathologic changes accompanied by progressive functional deficits closely mirroring the clinical trajectory in patients with DM1. Using this translationally relevant model, we evaluated the therapeutic efficacy of JUV-161. PanCUG960/+ mice received daily subcutaneous administration of JUV-161 at a dose of 12 mg/kg for 21 days. Treatment with JUV-161 significantly improved gastrocnemius muscle mass (180 mg vs 160 mg in vehicle, P < .01) and tibialis anterior muscle cross-sectional area (1.92E3 µm² vs 1.82E3 µm², P < .01) in male mice. Furthermore, treated animals demonstrated significant improvement in both specific forelimb grip strength (28.5 mN/g vs 23.2 mN/g in vehicle; P < .01) and all-limb grip strength (66.4 mN/g vs 56.1 mN/g in vehicle; P < .001). In contrast, vehicle-treated mice showed a steady decline in grip strength over the 3-week treatment period, indicating meaningful restoration of functional capacity with JUV-161. JUV-161 treatment also significantly lowered non-fasting blood glucose levels relative to baseline compared with vehicle treatment (−8.74% vs −0.04% in vehicle, P < .05). In conclusion, JUV-161 reverses both structural and functional manifestations of skeletal muscle myopathy in a robust and disease-relevant model of DM1. These findings support JUV-161 as a promising therapeutic candidate for treating DM1 and related muscle-wasting conditions.
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.
2026-04-03 | 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.
2026-01-22 | Nuclear MBL-1 modulates mitochondrial morphology through carnitine palmitoyltransferase in Caenorhabditis elegans with toxic trinucleotide repeats.
Expansion of nucleotide repeat sequences is linked to a growing number of neuromuscular degenerative disorders. Metabolic changes, including disruptions in mitochondrial function and dynamics, characterize these disorders and are believed to contribute to organismal toxicity. To investigate how toxic RNA repeats affect mitochondria, we used a Caenorhabditis elegans model that expresses expanded CUG repeat RNAs in muscle cells and recapitulates muscle dysfunction. We found that the RNA-binding protein Muscleblind-like 1 (MBL-1) is essential for normal mitochondrial function and regulates organelle morphology. In animals expressing expanded CUG repeats, where MBL-1 function is impaired, we identified two distinct mechanisms of mitochondrial disruption: altered mitochondrial morphology regulated by MBL-1, and oxidative phosphorylation (OxPhos) dysfunction occurring independently of MBL-1. Our data further show that changes in mitochondrial morphology are specifically linked to nuclear MBL-1 dysfunction, which affects cpt-3 expression, a gene encoding carnitine palmitoyltransferase-an enzyme required for fatty acid transport into mitochondria. This mechanism is conserved, with similar disruptions observed in patients with Myotonic Dystrophy type 1. Importantly, our findings indicate that increased organelle fragmentation is not central to cellular pathogenesis. Instead, OxPhos dysfunction appears to be a primary contributor to organismal toxicity.
2025-08-13 | MBNL Depletion Induces Muscle Stem Cell Activation and Myofibre Fusion while Impairing Myonuclear Maturation in Myotonic Dystrophy Type 1
Whether skeletal muscle in myotonic dystrophy type 1 (DM1) maintains its regenerative potential or shows inherent muscle stem cell (MuSC) defects remains unresolved. Here, we examine MuSC function in DM1 by combining an adult-onset Mbnl1/2 knockout mouse model with single-nucleus RNA sequencing (snRNA-seq) of human DM1 muscle biopsies. Loss of Mbnl in mouse myofibres triggers MuSC activation and fusion, resulting in central nuclear accumulation independent of degeneration. Lineage tracing confirms direct MuSC contribution to these nuclei, a process abolished upon MuSC ablation. In human DM1 specimens, we identify activated MuSCs and a myonuclear population with an immature transcriptional signature including expression of MuSC markers, and elevated DMPK levels. These findings imply that MuSCs in DM1 contribute to muscle repair by fusing into myofibres but give rise to immature myonuclei, likely due to toxic RNA effects on transcriptional reprogramming. Our study emphasises a previously overlooked role of MuSCs in DM1 pathology and identifies potential targets to support muscle regeneration.
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.
2026-06-16 | 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.
2026-06-06 | 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.
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.
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.
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.
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.
other
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.
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.
2024-12-24 | In Vivo-Like Scaffold-Free 3D In Vitro Models of Muscular Dystrophies: The Case for Anchored Cell Sheet Engineering in Personalized Medicine.
Progress in understanding the underlying mechanisms of muscular dystrophies is hindered by the lack of pathophysiologically relevant in vitro models. Here, an entirely scaffold-free anchored cell sheet engineering platform is used to create patient-specific three-dimensional (3D) skeletal muscle in vitro models. This approach effectively replicates mature muscle phenotypes and tissue- and disease-specific extracellular matric (ECM). Models were developed using primary cells from healthy individuals and patients with Duchenne Muscular Dystrophy and Myotonic Dystrophy Type 1. Through a combination of quantified histological staining (Hematoxylin & Eosin, Movat's Pentachrome, Masson's Trichrome) and immunostaining (desmin, myosin heavy chain, laminin, and dystrophin), it was demonstrated that the models formed mature constructs closely resembling their respective in vivo conditions. Proteomics analysis revealed that the models exhibited appropriate upregulation and downregulation of disease-relevant pathways. Models of diseased tissues accurately reflected key phenotypic features of the diseases, including alterations in muscle fiber integrity and ECM composition. Upon treatment with therapeutically beneficial drugs, significant changes in their proteomic profiles were documented, highlighting the models' potential for drug screening. This novel in vitro modeling approach, unlike other 3D techniques that rely on exogenous biomaterials that interfere with natural cellular behaviors, provides a promising platform for studying muscular dystrophies.
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.
2024-06-04 | Imperfect hairpins formed by CTG trinucleotide repeats are heteroduplex DNA molecules in living cells
Abstract There are over fifty microsatellite expansion disorders, often neurodegenerative pathologies, due to large expansions of tandem repeat sequences. These microsatellites vary in motif composition, size and copy number in the genome. The ability of these repeats to form secondary structures in vitro is strongly suspected to trigger the expansion process and therefore, the pathology. However, there is no formal proof that similar structures are formed in vivo , in living and replicating cells. We are focused on the CTG trinucleotide repeat whose expansion is responsible for myotonic dystrophy type 1 (DM1 or Steinert disease), affecting 1 in 8,000 people worldwide. A series of llama nanobodies (V H H) were selected to bind to the secondary structure formed by a synthetic imperfect CTG hairpin. Yeast one-hybrid was used to identify V H H that were able to activate a reporter gene in vivo . One of them was shown to be very specific since it binds a CTG hairpin but not a CAG hairpin or a GC-rich sequence. This nanobody also bind to long CTG trinucleotide repeats carried by plasmidic or genomic DNAs, proportionally to the number of repeats, suggesting that longer repeats tend to form more frequently imperfect hairpins. Finally, the V H H was bound to a protein G column and used to selectively enrich structure-containing DNA molecules, that were further observed by electron microscopy. They exhibit different kinds of structures in which only one strand is folded into an imperfect hairpin. Our results unambiguously show that alternative DNA structures are transiently formed by CTG trinucleotide repeats in living bacterial and yeast cells and suggest that imperfect CTG hairpins mainly exist in vivo mainly as heteroduplex DNA molecules.
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Drug Discovery Landscape
12 orphan drug designations for Steinert myotonic dystrophy.
12 orphan drug designations for Steinert myotonic dystrophy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
an antibody-siRNA conjugate, comprised of a humanized anti-TfR1 IgG1 monoclonal antibody covalently linked via a bis-maleimide non-cleavable linker to a double-stranded small interfering RNA directed to DMPK (myotonic dystrophy protein kinase) mRNA | other | FDA | ChainGen Biopharma Ltd. | |
mecasermin | proteins | FDA | — | Sarcomed AB |
Adeno-associated virus vector serotype SAN011 encoding a microRNA against DMPK mRNA | gene therapies | EMA | Sanofi B.V. | |
a phosphorodiamidate morpholino oligomer consisting of 7 repetitive cytosine, adenine, and guanine trimers conjugated via a polyethylene glycol-12 linker to a cyclic peptide and a linear peptide | oligonucleotides | FDA | Vertex Pharmaceuticals Incorporated | |
a nonreplicating adeno-associated virus, serotype SAN011 that expresses an artificial microRNA | gene therapies | FDA | Sanofi US Services Inc. | |
recombinant fusion protein (biologic) made by linking human serum albumin to a human Insulin-like growth factor 2 sequence | proteins | FDA | — | Juvena Therapeutics, Inc. |
Human transferrin 1 receptor (TfR1) targeting humanized IgG 1 kappa fragment antibody conjugated to an antisense oligonucleotide (ASO) | combination | FDA | Dyne Therapeutics, Inc. | |
a synthetic peptide-oligonucleotide conjugate in which a phosphorodiamidate morpholino oligonucleotide is conjugated to a cell penetrating peptide | oligonucleotides | FDA | PepGen Inc. | |
Humanised IgG1 kappa fragment antibody targeting TfR1 conjugated to P125 oligonucleotide | combination | EMA | Pharma Gateway AB | |
a lyophilized modified oligonucleotide of 16 nucleotides conjugated to a molecule of oleic acid | oligonucleotides | FDA | Arthex Biotech S.L. | |
an antibody oligonucleotide conjugate (AOC), comprised of a human transferrin receptor 1 (TfR1) targeting, effector function null, humanized IgG1 antibody (AV01mAb) conjugated to one small interfering RNA (siRNA). | antibodies | FDA | Avidity Biosciences | |
Tideglusib | small molecules | FDA | AMO Pharma Ltd. |
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