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Restorative treatments of dystrophin expression in Duchenne muscular dystrophy: A systematic review.Annals of Clinical and Translational... Sep 2020To evaluate the effect of pharmacological treatments that increase the synthesis of dystrophin in Duchenne muscular dystrophy (DMD). Systematic searches were carried out... (Meta-Analysis)
Meta-Analysis
To evaluate the effect of pharmacological treatments that increase the synthesis of dystrophin in Duchenne muscular dystrophy (DMD). Systematic searches were carried out in MEDLINE, EMBASE, and Web of Science, and in gray literature from inception to December 2019. Clinical trials addressing the effect of restorative treatments of dystrophin expression in children and adolescents with DMD on functional outcomes {(6-minute walking distance [6MWD], other timed functional tests [TFTs], The North Star Ambulatory Assessment)}, dystrophin expression, cardiorespiratory function, and biochemical tests were included. The DerSimonian-Laird method was used to calculate the pooled estimates for functional outcomes. Eleven studies were included in the systematic review and five in the meta-analysis. Eteplirsen showed a significant effect on 6MWD, Δ6MWD = 67.3 m (95% CI: 27.32, 107.28), and Δ6MWD = 151.0 m (95% CI: 36.15, 265.85) at 48 weeks and 3 years, respectively. In the systematic review, analyzing individually the clinical trials using Ataluren and Drisapersen showed a nonsignificant effect on 6MWD. However, the meta-analysis showed a significant effect on 6MWD for Ataluren and Drisapersen, Δ6MWD = 18.3 m (95% CI: 1.0, 35.5) and Δ6MWD = 21.5 m (95% CI: 4.7, 38.3), respectively. There were no significant differences according to baseline age for Drisapersen. Similarly, the meta-analysis showed effect in TFT with Ataluren. All drugs induced a partial synthesis of dystrophin, and exon skipping was obtained with Eteplirsen and Drisapersen. Eteplirsen also improved forced vital capacity (Δ%pFVC = 1.8%) and maximal inspiratory pressure (Δ%pMIP = 4.4%). Eteplirsen and Ataluren could modestly reduce disease progression. However, more trials are needed to confirm its efficacy, as well as quality of life and cost-utility studies.
Topics: Dystrophin; Humans; Morpholinos; Muscular Dystrophy, Duchenne; Oligonucleotides; Outcome Assessment, Health Care; Oxadiazoles
PubMed: 33325654
DOI: 10.1002/acn3.51149 -
Neuroscience and Biobehavioral Reviews Jun 2022Brain co-morbidities in DMD are well-documented, less is known about the cognitive, behavioral and psychosocial functioning of patients with BMD. (Review)
Review
BACKGROUND
Brain co-morbidities in DMD are well-documented, less is known about the cognitive, behavioral and psychosocial functioning of patients with BMD.
METHODS
The systematic review was carried out on two databases (Pubmed and Scopus) according to the PRISMA guidelines. We included all research articles specific to BMD written after 1995.
RESULTS
Studies examining neuropsychological and neurobehavioral functioning in BMD are few and have several methods limitations. BMD population is characterized by high rates of cognitive impairment, with specific involvement of different cognitive areas. Unlike DMD, verbal skills are better preserved. Neurodevelopmental and emotional/behavioral disorders have great importance in BMD, due to their high prevalence. Lack of Dp140 or Dp71 can cause intellectual disability, these isoforms are probably responsible for the other brain-related comorbidities as well.
DISCUSSION
The results suggest that cognitive and neuropsychiatric comorbid symptoms may affect a significant proportion of BMD patients therefore it is important to mental health and neuropsychological screening. Finding tools for an adequate assessment is a priority in order to include brain outcome measures in clinical trials.
Topics: Brain; Cognition; Dystrophin; Humans; Muscular Dystrophy, Duchenne; Protein Isoforms
PubMed: 35367224
DOI: 10.1016/j.neubiorev.2022.104648 -
Muscle & Nerve Mar 2022Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized... (Review)
Review
Duchenne muscular dystrophy (DMD) is associated with progressive muscle weakness, loss of ambulation (LOA), and early mortality. In this review we have synthesized published data on the clinical course of DMD by genotype. Using a systematic search implemented in Medline and Embase, 53 articles were identified that describe the clinical course of DMD, with pathogenic variants categorizable by exon skip or stop-codon readthrough amenability and outcomes presented by age. Outcomes described included those related to ambulatory, cardiac, pulmonary, or cognitive function. Estimates of the mean (95% confidence interval) age at LOA ranged from 9.1 (8.7-9.6) years among 90 patients amenable to skipping exon 53 to 11.5 (9.5-13.5) years among three patients amenable to skipping exon 8. Although function worsened with age, the impact of genotype was less clear for other outcomes (eg, forced vital capacity and left ventricular ejection fraction). Understanding the distribution of pathogenic variants is important for studies in DMD, as this research suggests major differences in the natural history of disease. In addition, specific details of the use of key medications, including corticosteroids, antisense oligonucleotides, and cardiac medications, should be reported.
Topics: Child; Dystrophin; Genotype; Humans; Muscular Dystrophy, Duchenne; Stroke Volume; Ventricular Function, Left
PubMed: 34878187
DOI: 10.1002/mus.27463 -
Orphanet Journal of Rare Diseases May 2021Duchenne muscular dystrophy (DMD) is a severe rare progressive inherited neuromuscular disorder, leading to loss of ambulation (LOA) and premature mortality. The... (Review)
Review
BACKGROUND
Duchenne muscular dystrophy (DMD) is a severe rare progressive inherited neuromuscular disorder, leading to loss of ambulation (LOA) and premature mortality. The standard of care for patients with DMD has been treatment with corticosteroids for the past decade; however a synthesis of contemporary data describing the clinical course of DMD is lacking. The objective was to summarize age at key clinical milestones (loss of ambulation, scoliosis, ventilation, cardiomyopathy, and mortality) in the corticosteroid-treatment-era.
METHODS
A systematic review was conducted using MEDLINE and EMBASE. The percentage experiencing key clinical milestones, and the mean or median age at those milestones, was synthesized from studies from North American populations, published between 2007 and 2018.
RESULTS
From 5637 abstracts, 29 studies were included. Estimates of the percentage experiencing key clinical milestones, and age at those milestones, showed heterogeneity. Up to 30% of patients lost ambulation by age 10 years, and up to 90% by 15 years of age. The mean age at scoliosis onset was approximately 14 years. Ventilatory support began from 15 to 18 years, and up to half of patients required ventilation by 20 years of age. Registry-based estimates suggest that 70% had evidence of cardiomyopathy by 15 years and almost all by 20 years of age. Finally, mortality rates up to 16% by age 20 years were reported; among those surviving to adulthood mortality was up to 60% by age 30 years.
CONCLUSIONS
Contemporary natural history studies from North America report that LOA on average occurs in the early teens, need for ventilation and cardiomyopathy in the late teens, and death in the third or fourth decade of life. Variability in rates may be due to differences in study design, treatment with corticosteroids or other disease-modifying agents, variations in clinical practices, and dystrophin mutations. Despite challenges in synthesizing estimates, these findings help characterize disease progression among contemporary North American DMD patients.
Topics: Adolescent; Adrenal Cortex Hormones; Adult; Cardiomyopathies; Child; Disease Progression; Dystrophin; Humans; Muscular Dystrophy, Duchenne; Young Adult
PubMed: 34022943
DOI: 10.1186/s13023-021-01862-w -
Diagnostics (Basel, Switzerland) Jan 2023Methodological advancements, such as relative haplotype and relative mutation dosage analyses, have enabled non-invasive prenatal diagnosis of autosomal recessive and... (Review)
Review
BACKGROUND
Methodological advancements, such as relative haplotype and relative mutation dosage analyses, have enabled non-invasive prenatal diagnosis of autosomal recessive and X-linked diseases. Duchenne muscular dystrophy (DMD) is an X-linked recessive disease characterized by progressive proximal muscular dystrophy and a high mortality rate before the age of twenty. We aimed to systematically present obtainable data regarding a non-invasive prenatal diagnosis of DMD and provide a comprehensive resume on the topic. The emphasis was given to the comparison of different available protocols and molecular methods used for fetal inheritance deduction, as well as their correlation with prognostic accuracy.
METHODS
We searched the Scopus and PubMed databases on 11 November 2022 and included articles reporting a non-invasive prenatal diagnosis of DMD in families at risk using relative dosage analysis methods.
RESULTS
Of the 342 articles identified, 7 met the criteria. The reported accuracy of NIPT for DMD was 100% in all of the studies except one, which demonstrated an accuracy of 86.67%. The combined accuracy for studies applying indirect RHDO, direct RHDO, and RMD approaches were 94.74%, 100%, and 100%, respectively. Confirmatory results by invasive testing were available in all the cases. Regardless of the technological complexity and low prevalence of the disease that reduces the opportunity for systematic research, the presented work demonstrates substantial accuracy of NIPT for DMD.
CONCLUSIONS
Attempts for its implementation into everyday clinical practice raise many ethical and social concerns. It is essential to provide detailed guidelines and arrange genetic counseling in order to ensure the proper indications for testing and obtain informed parental consent.
PubMed: 36672993
DOI: 10.3390/diagnostics13020183 -
Pharmacological Reports : PR Oct 2020Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular childhood disorder that causes progressive muscle weakness and degeneration and results in...
BACKGROUND
Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular childhood disorder that causes progressive muscle weakness and degeneration and results in functional decline, loss of ambulation and early death of young men due to cardiac or respiratory failure. Although the major cause of the disease has been known for many years-namely mutation in the DMD gene encoding dystrophin, one of the largest human genes-DMD is still incurable, and its treatment is challenging.
METHODS
A comprehensive and systematic review of literature on the gene, cell, and pharmacological experimental therapies aimed at restoring functional dystrophin or to counteract the associated processes contributing to disease progression like inflammation, fibrosis, calcium signaling or angiogenesis was carried out.
RESULTS
Although some therapies lead to satisfying effects in skeletal muscle, they are highly ineffective in the heart; therefore, targeting defective cardiac and respiratory systems is vital in DMD patients. Unfortunately, most of the pharmacological compounds treat only the symptoms of the disease. Some drugs addressing the underlying cause, like eteplirsen, golodirsen, and ataluren, have recently been conditionally approved; however, they can correct only specific mutations in the DMD gene and are therefore suitable for small sub-populations of affected individuals.
CONCLUSION
In this review, we summarize the possible therapeutic options and describe the current status of various, still imperfect, strategies used for attenuating the disease progression.
Topics: Animals; Dystrophin; Heart; Humans; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Mutation
PubMed: 32691346
DOI: 10.1007/s43440-020-00134-x -
African Journal of Traditional,... 2017Duchenne muscular dystrophy (DMD) is caused by a defective gene located on the X-chromosome, responsible for the production of the dystrophin protein. Complications in... (Review)
Review
BACKGROUND
Duchenne muscular dystrophy (DMD) is caused by a defective gene located on the X-chromosome, responsible for the production of the dystrophin protein. Complications in the musculoskeletal system have been previously described in DMD patients. Whole body vibration exercise (WBVE) is a treatment that improves musculoskeletal function in movement disorders. The aim of this study was to review the effects of WBVE on functional mobility, bone and muscle in DMD patients.
MATERIALS AND METHODS
Four databases were searched. Three eligible studies were found; all three conclude the management of DMD patients with WBV was clinically well tolerated. The studies used a side-alternating WBV system, frequencies 7 - 24 Hz; and amplitudes 2 - 4 mm.
RESULTS
A work indicates that a temporary increase in creatine kinase in DMD during the first days of WBV was observed, but other authors did not find changes. No significant changes in bone mass, muscle strength or bone markers. Some patients reported subjective functional improvement during training. Interpretation.
CONCLUSION
It is concluded that WBV seems to be a feasible and well tolerated exercise modality in DMD patients.
Topics: Exercise Therapy; Humans; Muscle Strength; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Range of Motion, Articular; Vibration
PubMed: 28740938
DOI: 10.21010/ajtcam.v14i4S.1 -
Journal of Managed Care & Specialty... Apr 2020Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM),... (Comparative Study)
Comparative Study
Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England States Consortium Systems Organization, Blue Cross Blue Shield of Massachusetts, Harvard Pilgrim Health Care, Kaiser Foundation Health Plan, and Partners HealthCare to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Agboola, Fluetsch, Rind, and Pearson are employed by ICER. Lin reports support from ICER during work on this economic model and grants from Mount Zion Health Fund, National Institutes of Health (National Cancer Institute and National Heart, Lung, and Blood Institute), and the Tobacco-Related Diseases Research Program, unrelated to this work. Walton reports support from ICER for work on this economic model and unrelated consulting fees from Baxter.
Topics: Cost-Benefit Analysis; Dystrophin; Exons; Humans; Immunosuppressive Agents; Models, Economic; Morpholinos; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; Prednisone; Pregnenediones; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 32223597
DOI: 10.18553/jmcp.2020.26.4.361 -
Frontiers in Bioengineering and... 2022As one of the most severe forms of muscle dystrophy, Duchenne muscular dystrophy (DMD) results in progressive muscle wasting, ultimately resulting in premature death due...
As one of the most severe forms of muscle dystrophy, Duchenne muscular dystrophy (DMD) results in progressive muscle wasting, ultimately resulting in premature death due to cardiomyopathy. In the many years of research, the solution to DMD remains palliative. Although numerous studies including clinical trials have provided promising results, approved drugs, even, the therapeutic window is still minimal with many shortcomings to be addressed. Logically, to combat DMD that arose from a single genetic mutation with gene therapy made sense. However, gene-based strategies as a treatment option are no stranger to drawbacks and limitations such as the size of the dystrophin gene and possibilities of vectors to elicit immune responses. In this systematic review, we aim to provide a comprehensive compilation on gene-based therapeutic strategies and critically evaluate the approaches relative to its efficacy and feasibility while addressing their current limitations. With the keywords "DMD AND Gene OR Genetic AND Therapy OR Treatment," we reviewed papers published in Science Direct, PubMed, and ProQuest over the past decade (2012-2021).
PubMed: 35402409
DOI: 10.3389/fbioe.2022.833833