Duchenne muscular dystrophy: Current treatment and emerging exon skipping and gene therapy approach

Patterson, Grant; Conner, Haley; Groneman, Mecham; Blavo, Cyril; Parmar, Mayur

doi:10.1016/j.ejphar.2023.175675

Cited by 32 publications

(14 citation statements)

References 32 publications

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“…Furthermore, long‐term corticosteroid use is associated with numerous side effects 1,3 . Exon‐skipping therapies can slow clinical decline, 4 but not all patients with DMD have mutations that are amenable to these treatments. Improved therapeutic options—with fewer adverse effects, greater efficacy, and broader applicability—are needed.…”

Section: Introductionmentioning

confidence: 99%

Long‐term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial

et al. 2023

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Introduction/AimsDelandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long‐term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild‐type protein) expression may positively alter disease progression in patients with DMD. We evaluated long‐term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD.MethodsAn open‐label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 1014 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests.ResultsFour patients (mean age, 5.1 years) were enrolled. There were 18 treatment‐related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9‐point difference in NSAA score, relative to a propensity‐score–weighted external control cohort (least‐squares mean [standard error] = 9.4 [3.4]; P = .0125).DiscussionGene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression.

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Section: Introductionmentioning

confidence: 99%

Long‐term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial

et al. 2023

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“… 54 The ongoing preclinical trials in canine models are supporting the treatment developments and options 55 , 56 , 57 and substantial advances have been made in a variety of treatments. 58 , 59 , 60 , 61 , 62 , 63 , 64 Defining the feline DMD variants supports the use of cats as a biomedical model in preclinical trials, like that of canine models.…”

Section: Discussionmentioning

confidence: 90%

Precision medicine using whole genome sequencing identifies a novel dystrophin (DMD) variant for X‐linked muscular dystrophy in a cat

Shelton,

Tucciarone,

Guo

et al. 2024

Veterinary Internal Medicne

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BackgroundMuscular dystrophies (MDs) are a large, heterogeneous group of degenerative muscle diseases. X‐linked dystrophin‐deficient MD in cats is the first genetically characterized cat model for a human disease and a few novel forms have been identified.Hypothesis/ObjectivesMuscular dystrophy was suspected in a young male domestic shorthair cat. Clinical, molecular, and genetic techniques could provide a definitive diagnosis.AnimalsA 1‐year‐old male domestic shorthair cat presented for progressive difficulty walking, macroglossia and dysphagia beginning at 6 months of age. The tongue was thickened, protruded with constant ptyalism, and thickening and rigidity of the neck and shoulders were observed.MethodsA complete neurological examination, baseline laboratory evaluation and biopsies of the trapezius muscle were performed with owner consent. Indirect immunofluorescence staining of muscle cryosections was performed using several monoclonal and polyclonal antibodies against dystrophy‐associated proteins. DNA was isolated for genomic analyses by whole genome sequencing and comparison to DNA variants in the 99 Lives Cat Genome Sequencing dataset.Results and Clinical ImportanceAspartate aminotransferase (687 IU/L) and creatine kinase (24 830 IU/L) activities were increased and mild hypokalemia (3.7 mmol/L) was present. Biopsy samples from the trapezius muscle confirmed a degenerative and regenerative myopathy and protein alterations identified by immunohistochemistry resulted in a diagnosis of a in dystrophin‐deficient form of X‐linked MD. A stop gain variant (c.4849C>T; p.Gln1617Ter) dystrophin was identified by genome sequencing. Precision/genomic medicine efforts for the domestic cat and in veterinary medicine support disease variant and animal model discovery and provide opportunities for targeted treatments for companion animals.

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“…In particular, gene silencing, gene transfer, or genome editing in muscle cells may limit the severity of myopathy. These approaches are promising for Duchenne muscular dystrophy [ 389 ] and ALS [ 390 ]. They can be further improved with inert nanocarriers that circumvent the adverse effects of viral vectors [ 391 , 392 ].…”

Section: Main Textmentioning

confidence: 99%

Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

Chu,

Xie,

Payan

et al. 2023

Mol Neurodegeneration

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The AAA+ ATPase valosin containing protein (VCP) is essential for cell and organ homeostasis, especially in cells of the nervous system. As part of a large network, VCP collaborates with many cofactors to ensure proteostasis under normal, stress, and disease conditions. A large number of mutations have revealed the importance of VCP for human health. In particular, VCP facilitates the dismantling of protein aggregates and the removal of dysfunctional organelles. These are critical events to prevent malfunction of the brain and other parts of the nervous system. In line with this idea, VCP mutants are linked to the onset and progression of neurodegeneration and other diseases. The intricate molecular mechanisms that connect VCP mutations to distinct brain pathologies continue to be uncovered. Emerging evidence supports the model that VCP controls cellular functions on multiple levels and in a cell type specific fashion. Accordingly, VCP mutants derail cellular homeostasis through several mechanisms that can instigate disease. Our review focuses on the association between VCP malfunction and neurodegeneration. We discuss the latest insights in the field, emphasize open questions, and speculate on the potential of VCP as a drug target for some of the most devastating forms of neurodegeneration.

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Duchenne muscular dystrophy: Current treatment and emerging exon skipping and gene therapy approach

Cited by 32 publications

References 32 publications

Long‐term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial

Long‐term safety and functional outcomes of delandistrogene moxeparvovec gene therapy in patients with Duchenne muscular dystrophy: A phase 1/2a nonrandomized trial

Precision medicine using whole genome sequencing identifies a novel dystrophin (DMD) variant for X‐linked muscular dystrophy in a cat

Valosin containing protein (VCP): initiator, modifier, and potential drug target for neurodegenerative diseases

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