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Drugs Sep 2023Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene... (Review)
Review
Delandistrogene moxeparvovec (delandistrogene moxeparvovec-rokl; ELEVIDYS) is an adeno-associated virus (AAV) vector-based gene therapy designed to deliver a gene encoding a micro-dystrophin protein [i.e. a shortened (138 kDa) version of the dystrophin protein expressed in normal muscle cells (427 kDa)] to all muscles involved in the pathology of Duchenne muscular dystrophy (DMD). Developed by Sarepta Therapeutics, it is the first gene therapy to be approved (in June 2023 under the Accelerated Approval pathway) for the treatment of DMD in the USA, where it is indicated for ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the dystrophin (DMD) gene. The recommended dose of delandistrogene moxeparvovec is 1.33 × 10 vector genomes per kg of body weight or 10 mL/kg body weight, administered as a single intravenous infusion. Delandistrogene moxeparvovec is undergoing clinical development in several countries/regions, including the EU and Japan. This article summarizes the milestones in the development of delandistrogene moxeparvovec leading to this first approval in the USA for the treatment of ambulatory paediatric patients aged 4 through 5 years with DMD and a confirmed mutation in the DMD gene.
Topics: Humans; Child; Dystrophin; Muscular Dystrophy, Duchenne; Genetic Therapy; Mutation; Muscles; Muscle, Skeletal
PubMed: 37566211
DOI: 10.1007/s40265-023-01929-x -
Neurologic Clinics Aug 2014The dystrophinopathies Duchenne and Becker muscular dystrophies (DMD and BMD) represent the most common inherited disorders of muscle. Improvements in cardiac care,... (Review)
Review
The dystrophinopathies Duchenne and Becker muscular dystrophies (DMD and BMD) represent the most common inherited disorders of muscle. Improvements in cardiac care, attention to respiratory function, and judicious use of spinal correction surgery have led to increased survival in the DMD population. Meanwhile, advances in molecular therapeutics have led to promising therapies that are in or are entering clinical trials. An understanding of the dystrophinopathies, and recent advances in their molecular diagnosis and treatment, is of benefit to practicing neurologists.
Topics: Dystrophin; Humans; Male; Muscular Dystrophy, Duchenne
PubMed: 25037084
DOI: 10.1016/j.ncl.2014.05.002 -
Molecular Therapy : the Journal of the... Oct 2018Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by dystrophin gene mutation. Conceptually, replacing the mutated gene with a normal one would cure... (Review)
Review
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.
Topics: Dependovirus; Dystrophin; Genetic Therapy; Genetic Vectors; Humans; Muscle, Skeletal; Muscular Dystrophy, Duchenne
PubMed: 30093306
DOI: 10.1016/j.ymthe.2018.07.011 -
The Lancet. Neurology Sep 2022Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene... (Review)
Review
Duchenne muscular dystrophy is an X-linked disease caused by the absence of functional dystrophin in the muscle cells. Major advances have led to the development of gene therapies, tools that induce exon skipping, and other therapeutic approaches, including treatments targeting molecular pathways downstream of the absence of functional dystrophin. However, glucocorticoids remain the only treatment unequivocally shown to slow disease progression, despite the adverse effects associated with their long-term use. Besides glucocorticoids, which are standard care, five compounds have received regulatory approval in some but not all jurisdictions, with further efficacy results being awaited. Several compounds with promising results in early-phase clinical trials have not met their efficacy endpoints in late-phase trials, but the clinical development of many other compounds is ongoing. The current landscape is complicated by the number of compounds in various stages of development, their various mechanisms of action, and their genotype-specific applicability. The difficulties of clinical development that arise from both the rarity and variability of Duchenne muscular dystrophy might be overcome in the future by use of sensitive biomarkers, natural history data, and ameliorated trial designs.
Topics: Dystrophin; Exons; Genetic Therapy; Genotype; Humans; Muscular Dystrophy, Duchenne
PubMed: 35850122
DOI: 10.1016/S1474-4422(22)00125-9 -
Comprehensive Physiology Jul 2015The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins,... (Review)
Review
The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, trigger instability of the plasma membrane, and myofiber loss. Mutations in dystrophin have been extensively cataloged, providing remarkable structure-function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches.
Topics: Animals; Dystrophin; Dystrophin-Associated Proteins; Genetic Therapy; Humans; Muscular Dystrophies
PubMed: 26140716
DOI: 10.1002/cphy.c140048 -
International Journal of Molecular... Feb 2022Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder with a prevalence of approximately 1 in 3500-5000 males. DMD manifests as... (Review)
Review
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder with a prevalence of approximately 1 in 3500-5000 males. DMD manifests as childhood-onset muscle degeneration, followed by loss of ambulation, cardiomyopathy, and death in early adulthood due to a lack of functional dystrophin protein. Out-of-frame mutations in the dystrophin gene are the most common underlying cause of DMD. Gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system is a promising therapeutic for DMD, as it can permanently correct DMD mutations and thus restore the reading frame, allowing for the production of functional dystrophin. The specific mechanism of gene editing can vary based on a variety of factors such as the number of cuts generated by CRISPR, the presence of an exogenous DNA template, or the current cell cycle stage. CRISPR-mediated gene editing for DMD has been tested both in vitro and in vivo, with many of these studies discussed herein. Additionally, novel modifications to the CRISPR system such as base or prime editors allow for more precise gene editing. Despite recent advances, limitations remain including delivery efficiency, off-target mutagenesis, and long-term maintenance of dystrophin. Further studies focusing on safety and accuracy of the CRISPR system are necessary prior to clinical translation.
Topics: Animals; CRISPR-Cas Systems; Disease Models, Animal; Dystrophin; Frameshift Mutation; Gene Editing; Humans; Male; Muscular Dystrophy, Duchenne; Reading Frames; Translational Research, Biomedical
PubMed: 35163754
DOI: 10.3390/ijms23031832 -
Nature Communications Dec 2021Genome editing therapy for Duchenne muscular dystrophy (DMD) holds great promise, however, one major obstacle is delivery of the CRISPR-Cas9/sgRNA system to skeletal...
Genome editing therapy for Duchenne muscular dystrophy (DMD) holds great promise, however, one major obstacle is delivery of the CRISPR-Cas9/sgRNA system to skeletal muscle tissues. In general, AAV vectors are used for in vivo delivery, but AAV injections cannot be repeated because of neutralization antibodies. Here we report a chemically defined lipid nanoparticle (LNP) system which is able to deliver Cas9 mRNA and sgRNA into skeletal muscle by repeated intramuscular injections. Although the expressions of Cas9 protein and sgRNA were transient, our LNP system could induce stable genomic exon skipping and restore dystrophin protein in a DMD mouse model that harbors a humanized exon sequence. Furthermore, administration of our LNP via limb perfusion method enables to target multiple muscle groups. The repeated administration and low immunogenicity of our LNP system are promising features for a delivery vehicle of CRISPR-Cas9 to treat skeletal muscle disorders.
Topics: Animals; CRISPR-Associated Protein 9; CRISPR-Cas Systems; Disease Models, Animal; Dystrophin; Exons; Gene Editing; Genetic Therapy; Humans; Liposomes; Mice; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Nanoparticles; Neuromuscular Diseases; RNA, Messenger
PubMed: 34880218
DOI: 10.1038/s41467-021-26714-w -
Neuromuscular Disorders : NMD Oct 2021Duchenne muscular dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle weakness. It is caused by a variety of DMD gene pathogenic variations... (Review)
Review
Duchenne muscular dystrophy (DMD) is a severe X-linked disease characterized by progressive muscle weakness. It is caused by a variety of DMD gene pathogenic variations (large deletions or duplications, and small mutations) which leads to the absence or to a decreased amount of dystrophin protein. The allelic Becker muscular dystrophy is characterized by later onset and milder muscle involvement, and other rarer phenotypes might also be associated, such as dilated cardiomyopathy, cognitive impairment, and other neurological signs. Following the identification of the genetic cause and the disease pathophysiology, innovative personalized therapies emerged. These can be categorized into two main groups: (1) therapies aiming at the restoration of dystrophin at the sarcolemma; (2) therapeutics dealing with secondary consequences of dystrophin deficiency. In this review we provide an overview about DMD genotype-phenotype correlation, and on main approaches to restore dystrophin as stop codon read-through, exon skipping, vector-mediated gene therapy, and genome-editing strategies, some of these are based on approved orphan drugs. Finally, we present the clinical potential of novel strategies combining therapies to correct the genetic defect and other approaches, targeting secondary downstream pathological cascade due to dystrophin deficiency.
Topics: Dystrophin; Exons; Genetic Therapy; Humans; Muscular Dystrophy, Duchenne; Mutation; Phenotype; Sarcolemma
PubMed: 34736624
DOI: 10.1016/j.nmd.2021.08.004 -
Neurology May 2020To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53... (Randomized Controlled Trial)
Randomized Controlled Trial
OBJECTIVE
To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping.
METHODS
Part 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.
RESULTS
Twelve 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, < 0.001) and a positive correlation (Spearman = 0.663; < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry.
CONCLUSION
Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization.
CLINICALTRIALSGOV IDENTIFIER
NCT02310906.
CLASSIFICATION OF EVIDENCE
This 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.
Topics: Administration, Intravenous; Adolescent; Child; Dose-Response Relationship, Drug; Double-Blind Method; Dystrophin; Fluorescent Antibody Technique; Humans; Male; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Oligonucleotides; Sequence Deletion
PubMed: 32139505
DOI: 10.1212/WNL.0000000000009233 -
Expert Review of Neurotherapeutics 2023Duchenne muscular dystrophy (DMD) is one of the most severe and devastating neuromuscular hereditary diseases with a male newborn incidence of 20 000 cases each year.... (Review)
Review
INTRODUCTION
Duchenne muscular dystrophy (DMD) is one of the most severe and devastating neuromuscular hereditary diseases with a male newborn incidence of 20 000 cases each year. The disease caused by mutations (exon deletions, nonsense mutations, intra-exonic insertions or deletions, exon duplications, splice site defects, and deep intronic mutations) in the DMD gene, progressively leads to muscle wasting and loss of ambulation. This situation is painful for both patients and their families, calling for an emergent need for effective treatments.
AREAS COVERED
In this review, the authors describe the state of the gene therapy approach in clinical trials for DMD. This therapeutics included gene replacement, gene substitution, RNA-based therapeutics, readthrough mutation, and the CRISPR approach.
EXPERT OPINION
Only a few drug candidates have yet been granted conditional approval for the treatment of DMD. Most of these therapies have only a modest capability to restore the dystrophin or improve muscle function, suggesting an important unmet need in the development of DMD therapeutics. Complementary genes and cellular therapeutics need to be explored to both restore dystrophin, improve muscle function, and efficiently reconstitute the muscle fibers in the advanced stage of the disease.
Topics: Infant, Newborn; Humans; Male; Muscular Dystrophy, Duchenne; Dystrophin; Mutation; Exons; Genetic Therapy
PubMed: 37602688
DOI: 10.1080/14737175.2023.2249607