Dataset Information

Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype.

ABSTRACT: Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population.Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other mutations.We first compared fifteen non-ambulant DMD patients carrying deletions theoretically treatable by exon 53 skipping (DMD-53) with fifteen closely age-matched DMD patients with mutations not treatable by exon 53 skipping (DMD-all-non-53) then with fifteen DMD patients carrying deletions not treatable by exon 53 skipping (DMD-del-non-53).We found that DMD-53 patients had a lower left ventricular ejection fraction, more contractures and they tend to have weaker grips and pinch strengths than other DMD patients. DMD-53 patients lost ambulation significantly younger than other DMD patients. This result was confirmed by comparing ages at loss of ambulation in all non-ambulant DMD patients of the DMD cohort identified in a molecular diagnostic lab.These prospective and retrospective data demonstrate that DMD-53 patients have clinically more severe phenotypes than other DMD patients.

SUBMITTER: Servais L

PROVIDER: S-EPMC5240539 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype.

Servais Laurent L Montus Marie M Guiner Caroline Le CL Ben Yaou Rabah R Annoussamy Mélanie M Moraux Amélie A Hogrel Jean-Yves JY Seferian Andreea M AM Zehrouni Karima K Le Moing Anne-Gaëlle AG Gidaro Teresa T Vanhulle Catherine C Laugel Vincent V Butoianu Nina N Cuisset Jean-Marie JM Sabouraud Pascal P Cances Claude C Klein Andrea A Leturcq France F Moullier Philippe P Voit Thomas T

Journal of neuromuscular diseases 20150901 3

<h4>Background</h4>Exon skipping therapy is an emerging approach in Duchenne Muscular Dystrophy (DMD). Antisense oligonucleotides that induce skipping of exon 51, 44, 45, or 53 are currently being evaluated in clinical trials. These trials were designed on the basis of data available in general DMD population.<h4>Objectives</h4>Our objective was to compare the clinical and functional statuses of non-ambulant DMD patients theoretically treatable by exon 53 skipping and of DMD patients with other ...[more]

PMID: 27858743

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Project description:ImportanceAn unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease.ObjectiveTo evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping.Design, setting, and participantsThis phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019.InterventionsParticipants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion.Main outcomes and measuresPrimary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function.ResultsOf the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit.Conclusions and relevanceSystemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed.Trial registrationClinicalTrials.gov Identifier: NCT02740972.

Project description:BackgroundClinical trials in Duchenne muscular dystrophy (DMD) focus primarily on ambulant patients. Results cannot be extrapolated to later disease stages due to a decline in targeted muscle tissue. In non-ambulant DMD patients, hand function is relatively preserved and crucial for daily-life activities. We used quantitative MRI (qMRI) to establish whether the thenar muscles could be valuable to monitor treatment effects in non-ambulant DMD patients.MethodsSeventeen non-ambulant DMD patients (range 10.2-24.1 years) and 13 healthy controls (range 9.5-25.4 years) underwent qMRI of the right hand at 3 T at baseline. Thenar fat fraction (FF), total volume (TV), and contractile volume (CV) were determined using 4-point Dixon, and T2water was determined using multiecho spin-echo. Clinical assessments at baseline (n = 17) and 12 months (n = 13) included pinch strength (kg), performance of the upper limb (PUL) 2.0, DMD upper limb patient reported outcome measure (PROM), and playing a video game for 10 min using a game controller. Group differences and correlations were assessed with non-parametric tests.ResultsTotal volume was lower in patients compared with healthy controls (6.9 cm3 , 5.3-9.0 cm3 vs. 13.0 cm3 , 7.6-15.8 cm3 , P = 0.010). CV was also lower in patients (6.3 cm3 , 4.6-8.3 cm3 vs. 11.9 cm3 , 6.9-14.6 cm3 , P = 0.010). FF was slightly elevated (9.7%, 7.3-11.4% vs. 7.7%, 6.6-8.4%, P = 0.043), while T2water was higher (31.5 ms, 30.0-32.6 ms vs. 28.1 ms, 27.8-29.4 ms, P < 0.001). Pinch strength and PUL decreased over 12 months (2.857 kg, 2.137-4.010 to 2.243 kg, 1.930-3.339 kg, and 29 points, 20-36 to 23 points, 17-30, both P < 0.001), while PROM did not (49 points, 36-57 to 44 points, 30-54, P = 0.041). All patients were able to play for 10 min at baseline or follow-up, but some did not comply with the study procedures regarding this endpoint. Pinch strength correlated with TV and CV in patients (rho = 0.72 and rho = 0.68) and controls (both rho = 0.89). PUL correlated with TV, CV, and T2water (rho = 0.57, rho = 0.51, and rho = -0.59).ConclusionsLow thenar FF, increased T2water , correlation of muscle size with strength and function, and the decrease in strength and function over 1 year indicate that the thenar muscles are a valuable and quantifiable target for therapy in later stages of DMD. Further studies are needed to relate these data to the loss of a clinically meaningful milestone.

Project description:BACKGROUND:Exon skipping has been considered a promising therapeutic approach for Duchenne muscular dystrophy (DMD). Eteplirsen received conditional approval in the United States in 2016. To date, no systematic reviews or meta-analyses of randomized controlled trials (RCTs) of exon skipping drugs have been published to determine the pooled estimates for the effect of exon skipping in treating DMD. METHODS:A systematic review and meta-analysis of double-blind RCTs comparing exon-skipping drugs with placebo in DMD was performed. Trials were identified by searching published and unpublished studies from electronically available databases and clinical trial registries through October 2017. The primary outcomes were changes in the 6-min walk test (6MWT) distance, North Star Ambulatory Assessment (NSAA) scores, and adverse events. Random-effects meta-analysis and assessment of risk of bias were performed. This systematic review was registered at PROSPERO (CRD42016037504). RESULTS:Five studies involving 322 participants were included, investigating eteplirsen in one and drisapersen in four studies. There were no changes in 6MWT distance (mean difference [MD] -?9.16, 95% confidence interval [CI] -?21.94 to 3.62) or NSAA scores (MD 1.20, 95% CI -?2.35 to 4.75) after 24 weeks of treatment in the exon-skipping group compared with placebo. Subgroup analysis for a 6 mg/kg weekly injection of drisapersen showed significant changes in the 6MWT, favoring drisapersen after 24 weeks (MD -?20.24; 95% CI -?39.59 to -?0.89). However, drisapersen resulted in a significant increase in injection site reactions (risk ratio [RR] 3.67, 95% CI 1.96 to 6.89, p?<?0.0001) and renal toxicity (RR 1.81, 95% CI 1.11 to 2.94, p?=?0.02). Risk of bias was high in two of the five studies, including the eteplirsen and one drisapersen study. CONCLUSIONS:Current available data do not show evidence that exon-skipping drugs are effective in DMD. Despite potential effectiveness when used at a specific dose, significant side effects were reported with drisapersen. The small number of RCTs with relatively small numbers of participants indicate the difficulty in conducting sufficiently powered studies of DMD. Prospectively planned meta-analysis and utilization of the real-world data may provide a more precise estimate of the effect of exon skipping in this disease.

Dataset Information

Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype.

Publications

Non-Ambulant Duchenne Patients Theoretically Treatable by Exon 53 Skipping have Severe Phenotype.

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