Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy

New England Journal of Medicine, Journal Year: 2023, Volume and Issue: 389(13), P. 1203 - 1210

Published: Sept. 27, 2023

We treated a 27-year-old patient with Duchenne's muscular dystrophy (DMD) recombinant adeno-associated virus (rAAV) serotype 9 containing d

Language: Английский

---

BMN 351-Induced Exon Skipping and Dystrophin Expression in Skeletal and Cardiac Muscle Lead to Preservation of Motor Function in a Mouse Model of Exon 51 Skip-Amenable Duchenne Muscular Dystrophy

Nucleic Acid Therapeutics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 7, 2025

Duchenne muscular dystrophy (DMD) is caused by mutations of the DMD gene that prevent expression functional dystrophin protein. BMN 351 an antisense oligonucleotide (ASO) designed to induce skipping exon 51 pre-mRNA and production internally deleted but dystrophin. We determined whether extended-term dosing leads skipping, production, improved motor function in hDMDdel52/mdx mice containing a human 52-deleted transgene. Weekly intravenous doses vehicle, 6 mg/kg 351, or 18 were administered for 25 weeks, samples analyzed 4 12 weeks post-dosing. produced dose-dependent levels heart quadriceps muscles, accompanied increases mean 17% 55% Compared with vehicle-treated mice, ameliorated DMD-related histopathologic changes gastrocnemius muscle heart. Both preserved fine kinematics, which was worse compared wild-type Liver demonstrated findings consistent ASO accumulation, are considered especially sensitive humans other non-clinical species. These results support further clinical development 351.

Language: Английский

---

Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: May 18, 2023

An N-of-1 trial was developed to deliver a dCas9-VP64 transgene designed upregulate the cortical dystrophin as custom therapy for Duchenne muscular dystrophy (DMD) patient. After showing signs of mild cardiac dysfunction and pericardial effusion, patient acutely decompensated sustained arrest six-days after dosing succumbed two-days later. Post-mortem examination revealed severe acute-respiratory distress syndrome with diffuse alveolar damage. Vector biodistribution data obtained minimal expression in liver. There no evidence AAV9 antibodies nor effector T cell reactivity. These findings demonstrate innate immune signaling capillary leak form toxicity an advanced DMD case treated high-dose rAAV gene therapy.

Language: Английский

---

Slow or fast: Implications of myofibre type and associated differences for manifestation of neuromuscular disorders

Acta Physiologica, Journal Year: 2023, Volume and Issue: 238(4)

Published: June 12, 2023

Abstract Many neuromuscular disorders can have a differential impact on specific myofibre type, forming the central premise of this review. The many different skeletal muscles in mammals contain spectrum slow‐ to fast‐twitch myofibres with varying levels protein isoforms that determine their distinctive contractile, metabolic, and other properties. variations functional properties across range classic ‘slow’ ‘fast’ are outlined, combined exemplars predominantly slow‐twitch soleus extensor digitorum longus muscles, species comparisons, techniques used study these Other intrinsic extrinsic differences discussed context slow fast myofibres. These include inherent susceptibility damage, myonecrosis, regeneration, plus nerves, extracellular matrix, vasculature, examined growth, ageing, metabolic syndrome, sexual dimorphism. emphasise importance carefully considering influence myofibre‐type composition manifestation various lifespan for both sexes. Equally, understanding responses due factors provide deep insight into precise molecular mechanisms initiate exacerbate disorders. This focus types is fundamental enhance translation clinical management therapies muscle

Language: Английский

---

Histone deacetylase inhibition with givinostat: a multi-targeted mode of action with the potential to halt the pathological cascade of Duchenne muscular dystrophy

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 6, 2025

Muscle repair and regeneration are complex processes. In Duchenne muscular dystrophy (DMD), these processes disrupted by the loss of functional dystrophin, a key part transmembrane dystrophin-associated glycoprotein that stabilizes myofibers, indirectly leading to progressive muscle wasting, subsequent ambulation, respiratory cardiac insufficiency, premature death. As DMD pathology, histone deacetylase (HDAC) activity is constitutively increased, epigenetic changes inhibition factors, chronic inflammation, fibrosis, adipogenesis. HDAC has consequently been investigated as therapeutic approach for dystrophies that, significantly, works independently from specific genetic mutations, making it potentially suitable all patients with DMD. This review discusses how addresses pathophysiology in multi-targeted mode action summarizes recent evidence on rationale givinostat, which now approved United States Food Drug Administration treatment aged 6 years older.

Language: Английский

---

Early Cardiac Dysfunction in Duchenne Muscular Dystrophy: A Case Report and Literature Update

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(4), P. 1685 - 1685

Published: Feb. 16, 2025

Duchenne Muscular Dystrophy (DMD) is a severe X-linked recessive disorder characterized by progressive muscle degeneration due to dystrophin deficiency. Cardiac involvement, particularly dilated cardiomyopathy, significantly impacts morbidity and mortality, typically manifesting after age 10. This case report presents rare instance of early-onset cardiac involvement in 3-year-old male with confirmed deletion exon 55 the gene. The patient developed cardiomyopathy at 3 years 8 months, left ventricular dysfunction despite early treatment corticosteroids, ACE inhibitors, beta-blockers. Genetic mechanisms genotype-phenotype correlations related were reviewed, highlighting emerging therapies such as skipping, vamorolone, ifetroban, rimeporide. Studies indicate that variants exons 12, 14-17, 31-42, 45, 48-49 are associated more impairment. emphasizes need for early, ongoing assessment personalized address disease heterogeneity. While current DMD care standards improve survival, optimizing management through intervention novel remains essential. Further research needed better understand outcomes patients DMD.

Language: Английский

---

Ion Channels of the Sarcolemma and Intracellular Organelles in Duchenne Muscular Dystrophy: A Role in the Dysregulation of Ion Homeostasis and a Possible Target for Therapy

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2229 - 2229

Published: Jan. 23, 2023

Duchenne muscular dystrophy (DMD) is caused by the absence of dystrophin protein and a properly functioning dystrophin-associated complex (DAPC) in muscle cells. DAPC components act as molecular scaffolds coordinating assembly various signaling molecules including ion channels. DMD shows significant change channels sarcolemma intracellular organelles and, above all, sarcoplasmic reticulum mitochondria regulating homeostasis, which necessary for correct excitation relaxation muscles. This review devoted to analysis current data on changes structure, functioning, regulation activity striated muscles their contribution disruption function development pathology. We note prospects therapy based targeting correction alleviation pathology, problems that arise interpretation obtained model dystrophin-deficient objects.

Language: Английский

---

Duchenne muscular dystrophy treatment with lentiviral vector containing mini‐dystrophin gene in vivo

MedComm, Journal Year: 2024, Volume and Issue: 5(1)

Published: Jan. 1, 2024

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 via viral vectors. However, low packaging capacity and immunogenicity of vectors have hampered their clinical application. Herein, we constructed four lentiviral with sequence-optimized genes driven muscle-specific promoters. The stably expressed mini-dystrophin C2C12 muscle cells vitro. To estimate treatment effect vivo, transferred into neonatal C57BL/10ScSn-

Language: Английский

---

A Novel CRISPR-Cas9 Strategy to Target DYSTROPHIN Mutations Downstream of Exon 44 in Patient-Specific DMD iPSCs

Cells, Journal Year: 2024, Volume and Issue: 13(11), P. 972 - 972

Published: June 4, 2024

Mutations in the

Language: Английский

---

Evolution and developmental functions of the dystrophin-associated protein complex: beyond the idea of a muscle-specific cell adhesion complex

Frontiers in Cell and Developmental Biology, Journal Year: 2023, Volume and Issue: 11

Published: June 13, 2023

The Dystrophin-Associated Protein Complex (DAPC) is a well-defined and evolutionarily conserved complex in animals. DAPC interacts with the F-actin cytoskeleton via dystrophin, extracellular matrix membrane protein dystroglycan. Probably for historical reasons that have linked its discovery to muscular dystrophies, function often described as limited muscle integrity maintenance by providing mechanical robustness, which implies strong cell-extracellular adhesion properties. In this review, phylogenetic functional data from different vertebrate invertebrate models will be analyzed compared explore molecular cellular functions of DAPC, specific focus on dystrophin. These reveals evolution paths cells are not intrinsically many features dystrophin domains been identified yet. adhesive properties also discussed reviewing available evidence common key complexes, such clustering, force transmission, mechanosensitivity mechanotransduction. Finally, review highlights developmental roles tissue morphogenesis basement (BM) assembly may indicate adhesion-independent functions.

Language: Английский

---