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Cureus Dec 2023AMONDYS 45 (casimersen) is an antisense oligonucleotide therapy used to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by a mutation in... (Review)
Review
AMONDYS 45 (casimersen) is an antisense oligonucleotide therapy used to treat Duchenne muscular dystrophy (DMD), a rare genetic disorder characterized by a mutation in the DMD gene. Symptoms include progressive muscle weakness, respiratory and cardiac complications, and premature death. Casimersen targets a specific mutation in the DMD gene that results in the absence of dystrophin protein, a key structural component of muscle fibers. While there is currently no cure for DMD, exon-skipping therapy works by restoring the reading frame of the mutated gene, allowing the production of a partially functional dystrophin protein. Clinical trials of casimersen have shown promising results in increasing dystrophin production, as measured by polymerase chain reaction (PCR) droplets when compared to placebo. In a randomized double-blind trial, patients who received casimersen had significantly higher dystrophin levels when compared to those who received placebo. Casimersen therapy is administered through repeated intravenous infusions, although the optimal dosage and duration of treatment are still under investigation. Based on the completed and ongoing clinical trials, casimersen has been well tolerated, with most adverse events being mild and unrelated to casimersen. In 2021, AMONDYS 45 (casimersen) received approval from the US Food and Drug Administration (FDA) for the treatment of Duchene muscular dystrophy in patients with a mutation of the DMD gene that is amenable to exon 45 skipping. These collective findings indicate that casimersen has the potential to elicit functional changes in individuals with DMD, although further studies are necessary to comprehensively evaluate the specific functional improvements. Regardless, the FDA approval and ongoing clinic trials mark a significant milestone in the development of DMD treatments and offer hope for those affected by this debilitating disease.
PubMed: 38283433
DOI: 10.7759/cureus.51237 -
Scientific Reports Jan 2024Human urine-derived cells (UDCs) are primary cultured cells originating from the upper urinary tract and are known to be multipotent. We previously developed...
Human urine-derived cells (UDCs) are primary cultured cells originating from the upper urinary tract and are known to be multipotent. We previously developed MYOD1-transduced UDCs (MYOD1-UDCs) as a model recapitulating the pathogenesis of Duchenne muscular dystrophy (DMD) caused by a lack of dystrophin. MYOD1-UDCs also allow evaluation of the efficacy of exon skipping with antisense oligonucleotides. However, despite the introduction of MYOD1, some MYOD1-UDCs failed to form myotubes, possibly because of heterogeneity among UDCs. Here, we carried out single-cell RNA-sequencing analyses and revealed that CD90/Thy-1 was highly expressed in a limited subpopulation of UDCs with high myogenic potency. Furthermore, CD90-positive MYOD1-UDCs, but not CD90-negative cells, could form myotubes expressing high levels of myosin heavy chain and dystrophin. Notably, overexpression of CD90 in CD90-negative MYOD1-UDCs did not enhance myogenic differentiation, whereas CD90 suppression in CD90-positive UDCs led to decreased myotube formation and decreased myosin heavy chain expression. CD90 may thus contribute to the fusion of single-nucleated MYOD1-UDCs into myotubes but is not crucial for promoting the expression of late muscle regulatory factors. Finally, we confirmed that CD90-positive MYOD1-UDCs derived from patients with DMD were a valuable tool for obtaining a highly reproducible and stable evaluation of exon skipping using antisense oligonucleotide.
Topics: Humans; Dystrophin; Myosin Heavy Chains; Muscular Dystrophy, Duchenne; Muscle Fibers, Skeletal; Oligonucleotides, Antisense; Sequence Analysis, RNA
PubMed: 38282008
DOI: 10.1038/s41598-024-52530-5 -
Genes & Diseases May 2024
PubMed: 38274373
DOI: 10.1016/j.gendis.2023.04.019 -
PloS One 2024ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and...
A phase 2 open-label study of the safety and efficacy of weekly dosing of ATL1102 in patients with non-ambulatory Duchenne muscular dystrophy and pharmacology in mdx mice.
BACKGROUND
ATL1102 is a 2'MOE gapmer antisense oligonucleotide to the CD49d alpha subunit of VLA-4, inhibiting expression of CD49d on lymphocytes, reducing survival, activation and migration to sites of inflammation. Children with DMD have dystrophin deficient muscles susceptible to contraction induced injury, which triggers the immune system, exacerbating muscle damage. CD49d is a biomarker of disease severity in DMD, with increased numbers of high CD49d expressing T cells correlating with more severe and progressive weakess, despite corticosteroid treatment.
METHODS
This Phase 2 open label study assessed the safety, efficacy and pharmacokinetic profile of ATL1102 administered as 25 mg weekly by subcutaneous injection for 24 weeks in 9 non-ambulatory boys with DMD aged 10-18 years. The main objective was to assess safety and tolerability of ATL1102. Secondary objectives included the effect of ATL1102 on lymphocyte numbers in the blood, functional changes in upper limb function as assessed by Performance of Upper Limb test (PUL 2.0) and upper limb strength using MyoGrip and MyoPinch compared to baseline.
RESULTS
Eight out of nine participants were on a stable dose of corticosteroids. ATL1102 was generally safe and well tolerated. No serious adverse events were reported. There were no participant withdrawals from the study. The most commonly reported adverse events were injection site erythema and skin discoloration. There was no statistically significant change in lymphocyte count from baseline to week 8, 12 or 24 of dosing however, the CD3+CD49d+ T lymphocytes were statistically significantly higher at week 28 compared to week 24, four weeks past the last dose (mean change 0.40x109/L 95%CI 0.05, 0.74; p = 0.030). Functional muscle strength, as measured by the PUL2.0, EK2 and Myoset grip and pinch measures, and MRI fat fraction of the forearm muscles were stable throughout the trial period.
CONCLUSION
ATL1102, a novel antisense drug being developed for the treatment of inflammation that exacerbates muscle fibre damage in DMD, appears to be safe and well tolerated in non-ambulant boys with DMD. The apparent stabilisation observed on multiple muscle disease progression parameters assessed over the study duration support the continued development of ATL1102 for the treatment of DMD.
TRIAL REGISTRATION
Clinical Trial Registration. Australian New Zealand Clinical Trials Registry Number: ACTRN12618000970246.
Topics: Male; Child; Animals; Mice; Humans; Muscular Dystrophy, Duchenne; Mice, Inbred mdx; Australia; Muscle, Skeletal; Adrenal Cortex Hormones; Inflammation
PubMed: 38271438
DOI: 10.1371/journal.pone.0294847 -
Cardiovascular Research Apr 2024A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) up-regulation contributes to the atrial electrical remodelling...
AIMS
A reduction in both dystrophin and neuronal nitric oxide synthase (NOS1) secondary to microRNA-31 (miR-31) up-regulation contributes to the atrial electrical remodelling that underpins human and experimental atrial fibrillation (AF). In contrast, patients with Duchenne muscular dystrophy (DMD), who lack dystrophin and NOS1 and, at least in the skeletal muscle, have raised miR-31 expression, do not have increase susceptibility to AF in the absence of left ventricular (LV) dysfunction. Here, we investigated whether dystrophin deficiency is also associated with atrial up-regulation of miR-31, loss of NOS1 protein, and increased AF susceptibility in young mdx mice.
METHODS AND RESULTS
Echocardiography showed normal cardiac structure and function in 12-13 weeks mdx mice, with no indication by assay of hydroxyproline that atrial fibrosis had developed. The absence of dystrophin in mdx mice was accompanied by an overall reduction in syntrophin and a lower NOS1 protein content in the skeletal muscle and in the left atrial and ventricular myocardium, with the latter occurring alongside reduced Nos1 transcript levels (exons 1-2 by quantitative polymerase chain reaction) and an increase in NOS1 polyubiquitination [assessed using tandem polyubiquitination pulldowns; P < 0.05 vs. wild type (WT)]. Neither the up-regulation of miR-31 nor the substantial reduction in NOS activity observed in the skeletal muscle was present in the atrial tissue of mdx mice. At difference with the skeletal muscle, the mdx atrial myocardium showed a reduction in the constitutive NOS inhibitor, caveolin-1, coupled with an increase in NOS3 serine1177 phosphorylation, in the absence of differences in the protein content of other NOS isoforms or in the relative expression NOS1 splice variants. In line with these findings, transoesophageal atrial burst pacing revealed no difference in AF susceptibility between mdx mice and their WT littermates.
CONCLUSION
Dystrophin depletion is not associated with atrial miR-31 up-regulation, reduced NOS activity, or increased AF susceptibility in the mdx mouse. Compared with the skeletal muscle, the milder atrial biochemical phenotype may explain why patients with DMD do not exhibit a higher prevalence of atrial arrhythmias despite a reduction in NOS1 content.
Topics: Animals; Muscular Dystrophy, Duchenne; Atrial Fibrillation; Mice, Inbred mdx; Nitric Oxide Synthase Type I; MicroRNAs; Disease Models, Animal; Dystrophin; Humans; Male; Mice, Inbred C57BL; Muscle, Skeletal; Heart Atria; Atrial Remodeling; Mice
PubMed: 38270932
DOI: 10.1093/cvr/cvae022 -
JAMA Network Open Jan 2024The US Food and Drug Administration approved eteplirsen for Duchenne muscular dystrophy (DMD) in 2016 based on a controversial pivotal study that demonstrated a limited...
IMPORTANCE
The US Food and Drug Administration approved eteplirsen for Duchenne muscular dystrophy (DMD) in 2016 based on a controversial pivotal study that demonstrated a limited effect on the surrogate measure of dystrophin production. Other DMD treatments in the same class followed.
OBJECTIVE
To assess how patients receiving novel DMD treatments in postapproval clinical settings compare with patients in the clinical trials.
DESIGN, SETTING, AND PARTICIPANTS
This cross-sectional study collected data on patients who initiated 1 of 4 novel DMD treatments (eteplirsen, golodirsen, viltolarsen, and casimersen) using national claims databases of commercially insured (Merative MarketScan and Optum's Clinformatics Data Mart Database [CDM]) and Medicaid patients between September 19, 2016, and March 31, 2022. Patients were followed for 1 year after the date of first use of any novel DMD treatment. In addition, patients in pivotal DMD drug trials were identified for comparison.
EXPOSURES
Age, sex, race and ethnicity, region, and DMD stage of patients receiving novel DMD treatment.
MAIN OUTCOME AND MEASURES
The main outcome was health care costs and drug discontinuation as measured using descriptive statistics.
RESULTS
A total of 223 routine care patients initiating novel DMD drugs (58 in MarketScan, 35 in CDM, and 130 in Medicaid) were identified. Among the 106 patients in the pivotal trials, the mean (SD) age was 8.5 (2.0) years (range, 4.0-13.0 years), which was younger than the mean age of patients in routine care (MarketScan: 13.7 [7.0] years [range, 1.8-33.3 years; P < .001]; CDM: 11.9 [5.7] years [range, 0.6-23.6 years; P < .001]; Medicaid: 13.4 [6.5] years [range, 1.8-46.1 years; P < .001]). The proportion of female patients identified in postapproval clinical settings was 2.9% (n = 1) in CDM (vs 34 male patients [97.1%]) and 1.5% (n = 2) in Medicaid (vs 128 male patients [98.5%]), which was not different from the pivotal trials. While nearly all patients in the pivotal trials had DMD disease stage 1 or 2 when initiating the DMD treatments (103 [97.2%]), in the postapproval clinical setting, slightly more than one-third of patients were in disease stage 3 or 4 (MarketScan, 17 [36.2%; P < .001]; CDM, 13 [41.9%; P < .001]; Medicaid, 54 [47.0%; P < .001]). The payer's cost for novel DMD treatments varied across the databases, with a mean (SD) of $634 764 ($607 101) in MarketScan, $482 749 ($582 350) in CDM, and $384 023 ($1 165 730) in Medicaid. Approximately one-third of routine care patients discontinued the treatments after approximately 7 months (mean [SD], 6.1 [4.4], 6.9 [3.9], and 7.2 [4.3] months in MarketScan, CDM, and Medicaid, respectively).
CONCLUSIONS AND RELEVANCE
These findings raise questions about the translation of DMD drug trial findings to routine care settings, with patients in routine care discontinuing the treatment within 1 year and payers incurring substantial expenses for these medications. More data are needed on whether these high costs are accompanied by corresponding clinical benefits.
Topics: United States; Humans; Female; Male; Infant; Child, Preschool; Child; Adolescent; Young Adult; Adult; Cross-Sectional Studies; Muscular Dystrophy, Duchenne; Data Warehousing; Behavior Therapy; Databases, Factual
PubMed: 38265797
DOI: 10.1001/jamanetworkopen.2023.53094 -
Proteomes Jan 2024This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field...
This perspective article is concerned with the question of how proteomics, which is a core technique of systems biology that is deeply embedded in the multi-omics field of modern bioresearch, can help us better understand the molecular pathogenesis of complex diseases. As an illustrative example of a monogenetic disorder that primarily affects the neuromuscular system but is characterized by a plethora of multi-system pathophysiological alterations, the muscle-wasting disease Duchenne muscular dystrophy was examined. Recent achievements in the field of dystrophinopathy research are described with special reference to the proteome-wide complexity of neuromuscular changes and body-wide alterations/adaptations. Based on a description of the current applications of top-down versus bottom-up proteomic approaches and their technical challenges, future systems biological approaches are outlined. The envisaged holistic and integromic bioanalysis would encompass the integration of diverse omics-type studies including inter- and intra-proteomics as the core disciplines for systematic protein evaluations, with sophisticated biomolecular analyses, including physiology, molecular biology, biochemistry and histochemistry. Integrated proteomic findings promise to be instrumental in improving our detailed knowledge of pathogenic mechanisms and multi-system dysfunction, widening the available biomarker signature of dystrophinopathy for improved diagnostic/prognostic procedures, and advancing the identification of novel therapeutic targets to treat Duchenne muscular dystrophy.
PubMed: 38250815
DOI: 10.3390/proteomes12010004 -
Frontiers in Veterinary Science 2023Pig growth is an important economic trait that involves the co-regulation of multiple genes and related signaling pathways. High-throughput sequencing has become a...
INTRODUCTION
Pig growth is an important economic trait that involves the co-regulation of multiple genes and related signaling pathways. High-throughput sequencing has become a powerful technology for establishing the transcriptome profiles and can be used to screen genome-wide differentially expressed genes (DEGs). In order to elucidate the molecular mechanism underlying muscle growth, this study adopted RNA sequencing (RNA-seq) to identify and compare DEGs at the genetic level in the longissimus dorsi muscle (LDM) between two indigenous Chinese pig breeds (Diannan small ears [DSE] pig and Wujin pig [WJ]) and one introduced pig breed (Landrace pig [LP]).
METHODS
Animals under study were from two Chinese indigenous pig breeds (DSE pig, = 3; WJ pig, = 3) and one introduced pig breed (LP, = 3) were used for RNA sequencing (RNA-seq) to identify and compare the expression levels of DEGs in the LDM. Then, functional annotation, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Protein-Protein Interaction (PPI) network analysis were performed on these DEGs. Then, functional annotation, Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, and Protein-Protein Interaction (PPI) network analysis were performed on these DEGs.
RESULTS
The results revealed that for the DSE, WJ, and LP libraries, more than 66, 65, and 71 million clean reads were generated by transcriptome sequencing, respectively. A total of 11,213 genes were identified in the LDM tissue of these pig breeds, of which 7,127 were co-expressed in the muscle tissue of the three samples. In total, 441 and 339 DEGs were identified between DSE vs. WJ and LP vs. DSE in the study, with 254, 193 up-regulated genes and 187, 193 down-regulated genes in DSE compared to WJ and LP. GO analysis and KEGG signaling pathway analysis showed that DEGs are significantly related to contractile fiber, sarcolemma, and dystrophin-associated glycoprotein complex, myofibril, sarcolemma, and myosin II complex, Glycolysis/Gluconeogenesis, Propanoate metabolism, and Pyruvate metabolism, etc. In combination with functional annotation of DEGs, key genes such as and were identified by PPI network analysis.
DISCUSSION
In conclusion, the present study revealed key genes including , and the unannotated new gene and related signaling pathways that influence the difference in muscle growth and could provide a theoretical basis for improving pig muscle growth traits in the future.
PubMed: 38249550
DOI: 10.3389/fvets.2023.1296208 -
The Journal of Reproduction and... Apr 2024The mammalian X chromosome exhibits enrichment in genes associated with germ cell development. Previously, we generated a rat model of Becker muscular dystrophy (BMD)...
The mammalian X chromosome exhibits enrichment in genes associated with germ cell development. Previously, we generated a rat model of Becker muscular dystrophy (BMD) characterized by an in-frame mutation in the dystrophin gene, situated on the X chromosome and responsible for encoding a protein crucial for muscle integrity. Male BMD rats are infertile owing to the absence of normal spermatids in the epididymis. Within the seminiferous tubules of BMD rats, elongated spermatids displayed abnormal morphology. To elucidate the cause of infertility, we identified a putative gene containing an open reading frame situated in the intronic region between exons 6 and 7 of the dystrophin gene, specifically deleted in male BMD rats. This identified gene, along with its encoded protein, exhibited specific detection within the testes, exclusively localized in round to elongated spermatids during spermiogenesis. Consequently, we designated the encoded protein as dystrophin-locus-derived testis-specific protein (DTSP). Given the absence of DTSP in the testes of BMD rats, we hypothesized that the loss of DTSP contributes to the infertility observed in male BMD rats.
Topics: Male; Rats; Animals; Testis; Dystrophin; Spermatogenesis; Proteins; Infertility; Mammals; Succinimides
PubMed: 38246612
DOI: 10.1262/jrd.2023-073