Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment.
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ABSTRACT:
SUBMITTER: Nowak KJ
PROVIDER: S-EPMC1299132 | biostudies-literature | 2004 Sep
REPOSITORIES: biostudies-literature
Publications
Duchenne muscular dystrophy and dystrophin: pathogenesis and opportunities for treatment.
Nowak Kristen J KJ Davies Kay E KE
EMBO reports 20040901 9
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Project description:Duchenne muscular dystrophy (DMD) is an X-linked hereditary disease characterized by progressive muscle wasting due to modifications in the DMD gene (exon deletions, nonsense mutations, intra-exonic insertions or deletions, exon duplications, splice site defects, and deep intronic mutations) that result in a lack of functional dystrophin expression. Many therapeutic approaches have so far been attempted to induce dystrophin expression and improve the patient phenotype. In this manuscript, we describe the relevant updates for some therapeutic strategies for DMD aiming to restore dystrophin expression. We also present and analyze in vitro and in vivo ongoing experimental approaches to treat the disease.
| S-EPMC8995704 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is an incurable X-linked recessive genetic disease caused by mutations in the dystrophin gene. Many researchers aim to restore truncated dystrophin via viral vectors. However, the low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral vectors with truncated and sequence-optimized dystrophin genes driven by muscle-specific promoters. The four lentiviral vectors stably expressed mini-dystrophin in C2C12 muscle cells in vitro. To estimate the treatment effect in vivo, we transferred the lentiviral vectors into neonatal C57BL/10ScSn-Dmdmdx mice through local injection. The levels of modified dystrophin expression increased, and their distribution was also restored in treated mice. At the same time, they exhibited the restoration of pull force and a decrease in the number of mononuclear cells. The remissions lasted 3-6 months in vivo. Moreover, no integration sites of vectors were distributed into the oncogenes. In summary, this study preliminarily demonstrated the feasibility and safety of lentiviral vectors with mini-dystrophin for DMD gene therapy and provided a new strategy to restore truncated dystrophin.
| S-EPMC10771042 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure the disease. However, this task has encountered significant challenges due to the enormous size of the gene and the distribution of muscle throughout the body. The former creates a hurdle for viral vector packaging and the latter begs for whole-body therapy. To address these obstacles, investigators have invented the highly abbreviated micro-dystrophin gene and developed body-wide systemic gene transfer with adeno-associated virus (AAV). Numerous microgene configurations and various AAV serotypes have been explored in animal models in many laboratories. Preclinical data suggests that intravascular AAV micro-dystrophin delivery can significantly ameliorate muscle pathology, enhance muscle force, and attenuate dystrophic cardiomyopathy in animals. Against this backdrop, several clinical trials have been initiated to test the safety and tolerability of this promising therapy in DMD patients. While these trials are not powered to reach a conclusion on clinical efficacy, findings will inform the field on the prospects of body-wide DMD therapy with a synthetic micro-dystrophin AAV vector. This review discusses the history, current status, and future directions of systemic AAV micro-dystrophin therapy.
| S-EPMC6171037 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD) is a serious genetic neuromuscular rare disease that is prevalent and caused by the mutation/deletion of the X-linked DMD gene that encodes dystrophin. Utrophin is a dystrophin homologous protein on human chromosome 6. Dystrophin and utrophin are highly homologous. They can recruit many dystrophin-glycoprotein complex (DGC)-related proteins and co-localize at the sarcolemma in the early stage of human embryonic development. Moreover, utrophin is overexpressed naturally at the mature myofiber sarcolemma in DMD patients. Therefore, utrophin is considered the most promising homologous protein to replace dystrophin. This review summarizes various modulating drugs and gene therapy approaches for utrophin replacement. As a universal method to treat DMD disease, utrophin has a promising therapeutic prospect and deserves further investigation.
| S-EPMC11197810 | biostudies-literature
Project description:Growing evidence demonstrates the crosstalk between the immune system and the skeletal muscle in inflammatory muscle diseases and dystrophic conditions such as Duchenne Muscular Dystrophy (DMD), as well as during normal muscle regeneration. The rising of inflammation and the consequent activation of the immune system are hallmarks of DMD: several efforts identified the immune cells that invade skeletal muscle as CD4+ and CD8+ T cells, Tregs, macrophages, eosinophils and natural killer T cells. The severity of muscle injury and inflammation dictates the impairment of muscle regeneration and the successive replacement of myofibers with connective and adipose tissue. Since immune system activation was traditionally considered as a consequence of muscular wasting, we recently demonstrated a defect in central tolerance caused by thymus alteration and the presence of autoreactive T-lymphocytes in DMD. Although the study of innate and adaptive immune responses and their complex relationship in DMD attracted the interest of many researchers in the last years, the results are so far barely exhaustive and sometimes contradictory. In this review, we describe the most recent improvements in the knowledge of immune system involvement in DMD pathogenesis, leading to new opportunities from a clinical point-of-view.
| S-EPMC8533196 | biostudies-literature
Project description:Duchenne muscular dystrophy is a devastating disease that leads to progressive muscle loss and premature death. While medical management focuses mostly on symptomatic treatment, decades of research have resulted in first therapeutics able to restore the affected reading frame of dystrophin transcripts or induce synthesis of a truncated dystrophin protein from a vector, with other strategies based on gene therapy and cell signaling in preclinical or clinical development. Nevertheless, recent reports show that potentially therapeutic dystrophins can be immunogenic in patients. This raises the question of whether a dystrophin paralog, utrophin, could be a more suitable therapeutic protein. Here, we compare dystrophin and utrophin amino acid sequences and structures, combining published data with our extended in silico analyses. We then discuss these results in the context of therapeutic approaches for Duchenne muscular dystrophy. Specifically, we focus on strategies based on delivery of micro-dystrophin and micro-utrophin genes with recombinant adeno-associated viral vectors, exon skipping of the mutated dystrophin pre-mRNAs, reading through termination codons with small molecules that mask premature stop codons, dystrophin gene repair by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (CRISPR/Cas9)-mediated genetic engineering, and increasing utrophin levels. Our analyses highlight the importance of various dystrophin and utrophin domains in Duchenne muscular dystrophy treatment, providing insights into designing novel therapeutic compounds with improved efficacy and decreased immunoreactivity. While the necessary actin and β-dystroglycan binding sites are present in both proteins, important functional distinctions can be identified in these domains and some other parts of truncated dystrophins might need redesigning due to their potentially immunogenic qualities. Alternatively, therapies based on utrophins might provide a safer and more effective approach.
| S-EPMC10789850 | biostudies-literature
Project description:BackgroundMyostatin is a potent muscle growth inhibitor that belongs to the Transforming Growth Factor-? (TGF-?) family. Mutations leading to non functional myostatin have been associated with hypermuscularity in several organisms. By contrast, Duchenne muscular dystrophy (DMD) is characterized by a loss of muscle fibers and impaired regeneration. In this study, we aim to knockdown myostatin by means of exon skipping, a technique which has been successfully applied to reframe the genetic defect of dystrophin gene in DMD patients.MethodsWe targeted myostatin exon 2 using antisense oligonucleotides (AON) in healthy and DMD-derived myotubes cultures. We assessed the exon skipping level, transcriptional expression of myostatin and its target genes, and combined myostatin and several dystrophin AONs. These AONs were also applied in the mdx mice models via intramuscular injections.ResultsMyostatin AON induced exon 2 skipping in cell cultures and to a lower extent in the mdx mice. It was accompanied by decrease in myostatin mRNA and enhanced MYOG and MYF5 expression. Furthermore, combination of myostatin and dystrophin AONs induced simultaneous skipping of both genes.ConclusionsWe conclude that two AONs can be used to target two different genes, MSTN and DMD, in a straightforward manner. Targeting multiple ligands of TGF-beta family will be more promising as adjuvant therapies for DMD.
| S-EPMC3107769 | biostudies-literature
Project description:ObjectiveTo report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.MethodsPart 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry.ResultsTwelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.ConclusionGolodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.Clinicaltrialsgov identifierNCT02310906.Classification of evidenceThis study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.
| S-EPMC7357297 | biostudies-literature
Project description:Duchenne muscular dystrophy (DMD)--which is caused by mutations in the dystrophin gene-is one of the most severe myopathies. Among therapeutic strategies, exon skipping allows the rescue of dystrophin synthesis through the production of a shorter but functional messenger RNA. Here, we report the identification of a microRNA--miR-31--that represses dystrophin expression by targeting its 3' untranslated region. In human DMD myoblasts treated with exon skipping, we demonstrate that miR-31 inhibition increases dystrophin rescue. These results indicate that interfering with miR-31 activity can provide an ameliorating strategy for those DMD therapies that are aimed at efficiently recovering dystrophin synthesis.
| S-EPMC3049433 | biostudies-literature
Project description:A few animal models of Duchenne muscular dystrophy (DMD) are available, large ones such as pigs or dogs being expensive and difficult to handle. Mdx (X-linked muscular dystrophy) mice only partially mimic the human disease, with limited chronic muscular lesions and muscle weakness. Their small size also imposes limitations on analyses. A rat model could represent a useful alternative since rats are small animals but 10 times bigger than mice and could better reflect the lesions and functional abnormalities observed in DMD patients. Two lines of Dmd mutated-rats (Dmdmdx) were generated using TALENs targeting exon 23. Muscles of animals of both lines showed undetectable levels of dystrophin by western blot and less than 5% of dystrophin positive fibers by immunohistochemistry. At 3 months, limb and diaphragm muscles from Dmdmdx rats displayed severe necrosis and regeneration. At 7 months, these muscles also showed severe fibrosis and some adipose tissue infiltration. Dmdmdx rats showed significant reduction in muscle strength and a decrease in spontaneous motor activity. Furthermore, heart morphology was indicative of dilated cardiomyopathy associated histologically with necrotic and fibrotic changes. Echocardiography showed significant concentric remodeling and alteration of diastolic function. In conclusion, Dmdmdx rats represent a new faithful small animal model of DMD.
| S-EPMC4195719 | biostudies-literature