<i>DMD</i>
            genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

Bello, Luca; Morgenroth, Lauren P.; Gordish‐Dressman, Heather; Hoffman, Eric P.; McDonald, Craig M.; Çırak, Sebahattin

doi:10.1212/wnl.0000000000002891

Cited by 132 publications

(130 citation statements)

References 39 publications

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“…Clinical and genetic heterogeneity in DMD has been well-described 25 , 26 , 27 and it has previously been noted that cognitive outcomes may predict motor, cardiac and respiratory outcomes in DMD 28 . Boys with DMD who had poor cognition, also had worse cardiac outcome, with two-thirds of these boys having cardiac involvement before age 12.…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS).

Thangarajh¹,

Spurney²,

Gordish‐Dressman³

et al. 2018

PLoS Curr

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Introduction: Duchenne muscular dystrophy (DMD) is the most common X-linked neuromuscular condition manifested by progressive skeletal muscle weakness, cardiopulmonary involvement and cognitive deficits. Neurodevelopmental symptoms and signs are under-appreciated in this population despite the recognition that cognition has a major impact on quality-of-life. We describe the neurodevelopmental needs in a large cohort of young boys with DMD from the DMD Natural History Study (DNHS). We explore the association between neurodevelopmental needs and DMD mutation location, and with glucocorticoid use. Methods: We prospectively evaluated 204 participants between ages 4 to less than 9 years of age with DMD as part of a large, longitudinal, international DNHS. We obtained parent- or primary care-giver report of neurodevelopmental needs as part of their study visit. We assessed the relationship between parent/care-giver neurodevelopmental needs and DMD mutation location, and glucocorticoid use.Results: The neurodevelopmental needs that were most commonly reported included speech delay (33%), mild developmental delay (24%), significant behavioral problems (16.5%), language impairment (14.5%), learning disability (14.5%), attention-deficit hyperactivity disorder (5%) and autism spectrum disorder (3%). Neurodevelopmental needs were more commonly reported by care-givers in those with DMD mutations downstream of exon 51. There was no relationship between care-giver reported neurodevelopmental needs and glucocorticoid use.Conclusion: Neurodevelopmental needs are highly prevalent in young boys with DMD. Care-givers report higher neurodevelopmental needs when subjects have DMD mutations downstream of exon 51. Early interventions aimed at cognitive health are critical to improve the quality-of-life of individuals with DMD.Trial Registration: ClinicalTrials.gov NCT00468832

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Section: Discussionmentioning

confidence: 99%

Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS).

Thangarajh¹,

Spurney²,

Gordish‐Dressman³

et al. 2018

PLoS Curr

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“…1 DMD is progressive, beginning with loss of ambulation between age 9 and 14 years, followed by respiratory complications and cardiac function decline, and ending in death. [3][4][5] As standard of care options have changed, disease progression has improved. 6 Corticosteroids have been reported to reduce inflammation 7 and to delay the loss of ambulation (by approximately 3 years) and the decline of respiratory function.…”

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confidence: 99%

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

et al. 2020

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IMPORTANCE Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). OBJECTIVE To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. DESIGN, SETTING, AND PARTICIPANTS This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children's Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (Ն12 weeks). INTERVENTIONS A single dose of 2.0 × 10 14 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). MAIN OUTCOMES AND MEASURES Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. RESULTS Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. CONCLUSIONS AND RELEVANCE This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03375164

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“…Functional improvements due to natural growth are observed in boys younger than age 7, until the characteristic degeneration and loss of muscle tissue outpaces maturational development and physical growth (Mazzone et al , 2013, McDonald et al , 2010). As muscle deterioration overtakes muscle growth, patients with DMD have difficulty walking during childhood and become wheelchair dependent by their early teens(Bello et al , 2016, Flanigan, 2014, Guiraud et al , 2015, Kole and Krieg, 2015, Mazzone et al , 2011, Nigro et al , 1983). These patients continue to lose upper extremity function and require progressively more assisted ventilation during the teenage years (Guiraud et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification

Wilson¹,

Faelan²,

Patterson-Kane³

et al. 2017

Toxicol Pathol

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Duchenne and Becker muscular dystrophies (DMD/BMD) are neuromuscular disorders that primarily affect boys due to an X-linked mutation in the DMD gene, resulting in reduced to near absence of dystrophin or expression of truncated forms of dystrophin. Some newer therapeutic interventions aim to increase sarcolemmal dystrophin expression, and accurate dystrophin quantification is critical for demonstrating pharmacodynamic relationships in preclinical studies and clinical trials. Current challenges with measuring dystrophin include the variation in protein expression within individual muscle fibers and across whole muscle samples, the presence of pre-existing dystrophin-positive revertant fibers, and trace amounts of residual dystrophin. Immunofluorescence quantification of dystrophin can overcome many of these challenges, but manual quantification of protein expression may be complicated by variations in the collection of images, reproducible scoring of fluorescent intensity, and bias introduced by manual scoring of typically only a few high-power fields. This review highlights the pathology of DMD/BMD, discusses animal models of DMD/BMD, and describes dystrophin biomarker quantitation in DMD/BMD, with several image analysis approaches, including a new automated method, that evaluates protein expression of individual muscle fibers.

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DMD genotypes and loss of ambulation in the CINRG Duchenne Natural History Study

Abstract: As exon 44 skipping-amenable DMD has a later LoA, mutation-specific randomization and selection of placebo groups are essential for the success of clinical trials.

Cited by 132 publications

References 39 publications

Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS).

Neurodevelopmental Needs in Young Boys with Duchenne Muscular Dystrophy (DMD): Observations from the Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DNHS).

Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy

Duchenne and Becker Muscular Dystrophies: A Review of Animal Models, Clinical End Points, and Biomarker Quantification

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