scholarly journals P.076 Safety of Eteplirsen, a phosphorodiamidate morpholino oligomer, in Duchenne Muscular Dystrophy patients amenable to Exon 51 skipping

2018 ◽  
Vol 45 (s2) ◽  
pp. S36-S36
Author(s):  
J Mah ◽  
J Lynch ◽  
C Campbell
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Nasal Congestion ◽  
Functional Decline ◽  
Transient Temperature ◽  
Upper Respiratory Tract ◽  
Facial Flushing ◽  
Reading Frame ◽  
Upper Respiratory

Background: Duchenne muscular dystrophy (DMD) is an X-linked disorder affecting 1:3500-5000 live male births, causing a life-limiting form of muscular dystrophy. Whole exon deletions disrupting the reading frame result in near-absence of sarcolemmal dystrophin, essential for muscle function. Eteplirsen is a phosphorodiamidate morpholino oligomer (PMO) designed to induce production of internally-truncated dystrophin in certain patients. Methods: As of June 2016, 150 patients (4-19 years of age) with DMD received eteplirsen in 7 clinical trials. 143 patients received ≥1 intravenous infusion of eteplirsen (range: 0.5 - 50 mg/kg). 81 (54%) received treatment for ≥1 year (Range: 1-4+ years). Results: Common (>15%) adverse events (AEs) were cough, headache, vomiting, back pain, extremity pain, contusion, nasopharyngitis, upper respiratory tract infection, nasal congestion, arthralgia and rash. Non-serious facial flushing, erythema and mild transient temperature elevation occurred with eteplirsen. 10 (6.7%) patients experienced severe AEs; 12 (8%) patients experienced serious AEs. All serious and all but 1 severe AEs were considered unrelated to eteplirsen by the treating physicians. Serial echocardiograms in 12 treated patients demonstrated no functional decline over 4+ years. Conclusions: Eteplirsen’s tolerability will continue to be assessed in ongoing clinical trials.An updated data summary will be presented.

Chemistry and Pharmacology of Deflazacort: A Novel Bioactive Compound for the Treatment of Duchenne Muscular Dystrophy-A Mini Review

2019 ◽  
Vol 15 (1) ◽  
pp. 41-44 ◽  
Author(s):  
Mohammad Zeeshan ◽  
Arvind Kumar ◽  
Jagdish K. Sahu ◽  
Amrita Mishra ◽  
Arun K. Mishra
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Genetic Disorders ◽  
Bioactive Compound ◽  
Structural Similarity ◽  
Upper Respiratory Tract ◽  
Synthetic Compound ◽  
Progressive Degeneration ◽  
Upper Respiratory ◽  
Work Done

Objective: Firstly, Deflazacort was synthesized in 1969 and has the structural similarity with cortisol. The present review is an attempt to summarize the updated information related to chemistry and pharmacology of Deflazacort. Development: Deflazacort a synthetic compound synthesized by derivatization in the chemical structure of prednisolone with an aim to improve its potency. Deflazacort is under global development with Marathon Pharmaceuticals, was approved by the U.S. Food and Drug Administration in year 2017 to treat patients with Duchenne muscular dystrophy (DMD). Chemistry and Pharmacology: DMD is one of the rare and genetic disorders with the symptoms of progressive degeneration of muscle tissue. Chemically, it is deacetylated at position 21 to produce active metabolite 21-desacetyl deflazacort (21-desDFZ), which acts through the glucocorticoid receptor. The predominant side effects are cushingoid appearance, increased appetite, upper respiratory tract infection (URTI), pollakiuria, hirsutism, and nasopharyngitis. Conclusion: The present article summarizes the available updated information and work done so far on Deflazacort with special emphasis on its chemistry, pharmacology with detailed mechanism of action, pharmacodynamics, pharmacokinetics, metabolism and clinical trials etc.

scholarly journals Genotype characterization and delayed loss of ambulation by glucocorticoids in a large cohort of patients with Duchenne muscular dystrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Shu Zhang ◽  
◽  
Dongdong Qin ◽  
Liwen Wu ◽  
Man Li ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Hazard Ratio ◽  
Large Cohort ◽  
Muscle Disease ◽  
Clinical Progression ◽  
Large Deletions ◽  
The Mean ◽  
Lower Hazard

Abstract Background Duchenne muscular dystrophy (DMD) is the most common genetic muscle disease in human. We aimed to describe the genotype distribution in a large cohort of Chinese DMD patients and their delayed loss of ambulation by glucocorticoid (GC) treatments. This is to facilitate protocol designs and outcome measures for the emerging DMD clinical trials. Results A total of 1163 patients with DMD were recruited and genotyped. Genotype variations were categorized as large deletions, large duplications, and small mutations. Large deletions were further analyzed for those amenable to exon-skipping therapies. Participants aged 5 years or older were grouped into GC-treated and GC-naïve groups. Clinical progression among different genotypes and their responses to GC treatments were measured by age at loss of ambulation (LOA). Among the mutation genotypes, large deletions, large duplications, and small mutations accounted for 68.79%, 7.14%, and 24.07%, respectively. The mean age at diagnosis was 4.59 years; the median ages at LOA for the GC-naïve, prednisone/prednisolone-treated, and deflazacort-treated groups were 10.23, 12.02, and 13.95 years, respectively. The “deletion amenable to skipping exon 44” subgroup and the nonsense-mutation subgroup had older ages at LOA than the “other deletions” subgroup. Subgroups were further analyzed by both genotypes and GC status. All genotypes showed significant beneficial responses to GC treatment. Deletions amenable to skipping exon 44 showed a lower hazard ratio (0.155). The mean age at death was 18.57 years in this DMD group. Conclusion Genotype variation influences clinical progression in certain DMD groups. Beneficial responses to GC treatment were observed among all DMD genotypes. Compared with other genotypes, deletions amenable to skipping exon 44 had a lower hazard ratio, which may indicate a stronger protective effect of GC treatments on this subgroup. These data are valuable for designing future clinical trials, as clinical outcomes may be influenced by the genotypes.

scholarly journals Evaluating the potential of novel genetic approaches for the treatment of Duchenne muscular dystrophy

2021 ◽  
Author(s):  
Vratko Himič ◽  
Kay E. Davies
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Structural Integrity ◽  
Viral Vector ◽  
Exon Skipping ◽  
Dystrophin Gene ◽  
Pharmacological Treatments ◽  
Genetic Sequencing ◽  
Reading Frame ◽  
Target Effects

AbstractDuchenne muscular dystrophy (DMD) is an X-linked progressive muscle-wasting disorder that is caused by a lack of functional dystrophin, a cytoplasmic protein necessary for the structural integrity of muscle. As variants in the dystrophin gene lead to a disruption of the reading frame, pharmacological treatments have only limited efficacy; there is currently no effective therapy and consequently, a significant unmet clinical need for DMD. Recently, novel genetic approaches have shown real promise in treating DMD, with advancements in the efficacy and tropism of exon skipping and surrogate gene therapy. CRISPR-Cas9 has the potential to be a ‘one-hit’ curative treatment in the coming decade. The current limitations of gene editing, such as off-target effects and immunogenicity, are in fact partly constraints of the delivery method itself, and thus research focus has shifted to improving the viral vector. In order to halt the loss of ambulation, early diagnosis and treatment will be pivotal. In an era where genetic sequencing is increasingly utilised in the clinic, genetic therapies will play a progressively central role in DMD therapy. This review delineates the relative merits of cutting-edge genetic approaches, as well as the challenges that still need to be overcome before they become clinically viable.

scholarly journals In vivo non-invasive monitoring of dystrophin correction in a new Duchenne muscular dystrophy reporter mouse

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Leonela Amoasii ◽  
Hui Li ◽  
Yu Zhang ◽  
Yi-Li Min ◽  
Efrain Sanchez-Ortiz ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Genetic Disorder ◽  
Dystrophin Gene ◽  
Luciferase Reporter ◽  
Luciferase Expression ◽  
Gene Correction ◽  
Reading Frame ◽  
Non Invasive

Abstract Duchenne muscular dystrophy (DMD) is a fatal genetic disorder caused by mutations in the dystrophin gene. To enable the non-invasive analysis of DMD gene correction strategies in vivo, we introduced a luciferase reporter in-frame with the C-terminus of the dystrophin gene in mice. Expression of this reporter mimics endogenous dystrophin expression and DMD mutations that disrupt the dystrophin open reading frame extinguish luciferase expression. We evaluated the correction of the dystrophin reading frame coupled to luciferase in mice lacking exon 50, a common mutational hotspot, after delivery of CRISPR/Cas9 gene editing machinery with adeno-associated virus. Bioluminescence monitoring revealed efficient and rapid restoration of dystrophin protein expression in affected skeletal muscles and the heart. Our results provide a sensitive non-invasive means of monitoring dystrophin correction in mouse models of DMD and offer a platform for testing different strategies for amelioration of DMD pathogenesis.

scholarly journals Applications of CRISPR/Cas9 for the Treatment of Duchenne Muscular Dystrophy

2018 ◽  
Vol 8 (4) ◽  
pp. 38 ◽  
Author(s):  
Kenji Lim ◽  
Chantal Yoon ◽  
Toshifumi Yokota
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Wide Spectrum ◽  
Membrane Integrity ◽  
Dystrophin Gene ◽  
Muscle Membrane ◽  
Reading Frame ◽  
Long Term Treatment

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disease prevalent in 1 in 3500 to 5000 males worldwide. As a result of mutations that interrupt the reading frame of the dystrophin gene (DMD), DMD is characterized by a loss of dystrophin protein that leads to decreased muscle membrane integrity, which increases susceptibility to degeneration. CRISPR/Cas9 technology has garnered interest as an avenue for DMD therapy due to its potential for permanent exon skipping, which can restore the disrupted DMD reading frame in DMD and lead to dystrophin restoration. An RNA-guided DNA endonuclease system, CRISPR/Cas9 allows for the targeted editing of specific sequences in the genome. The efficacy and safety of CRISPR/Cas9 as a therapy for DMD has been evaluated by numerous studies in vitro and in vivo, with varying rates of success. Despite the potential of CRISPR/Cas9-mediated gene editing for the long-term treatment of DMD, its translation into the clinic is currently challenged by issues such as off-targeting, immune response activation, and sub-optimal in vivo delivery. Its nature as being mostly a personalized form of therapy also limits applicability to DMD patients, who exhibit a wide spectrum of mutations. This review summarizes the various CRISPR/Cas9 strategies that have been tested in vitro and in vivo for the treatment of DMD. Perspectives on the approach will be provided, and the challenges faced by CRISPR/Cas9 in its road to the clinic will be briefly discussed.

scholarly journals CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy

Genes ◽  
2020 ◽  
Vol 11 (3) ◽  
pp. 342 ◽  
Author(s):  
Kenji Rowel Q. Lim ◽  
Quynh Nguyen ◽  
Kasia Dzierlega ◽  
Yiqing Huang ◽  
Toshifumi Yokota
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Animal Models ◽  
Mechanical Stress ◽  
Muscle Cell ◽  
Neuromuscular Disorder ◽  
Reading Frame ◽  
Advantages And Disadvantages ◽  
Short Palindromic Repeat ◽  
Dmd Gene

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose well to some extent, each has its own limitations. To help overcome this, clustered regularly interspaced short palindromic repeat (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

P.13.14 Future clinical and biomarker development for SMTC1100, the first utrophin modulator to enter clinical trials for Duchenne Muscular Dystrophy (DMD)

2013 ◽  
Vol 23 (9-10) ◽  
pp. 813 ◽  
Author(s):  
J.M. Tinsley ◽  
N. Robinson ◽  
F.X. Wilson ◽  
G. Horne ◽  
R.J. Fairclough ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy

Development of a CRISPR/Cas9-mediated gene editing platform to restore the reading frame for 60% of Duchenne muscular dystrophy patients

2016 ◽  
Vol 26 ◽  
pp. S127-S128
Author(s):  
C. Young ◽  
M. Hicks ◽  
N. Ermolova ◽  
H. Nakano ◽  
M. Jan ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Gene Editing ◽  
Reading Frame
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