Summary Background We report clinical safety and biochemical efficacy from a dose-ranging study of intravenously administered AVI-4658 phosphorodiamidate morpholino oligomer (PMO) in patients with ...Duchenne muscular dystrophy. Method We undertook an open-label, phase 2, dose-escalation study (0·5, 1·0, 2·0, 4·0, 10·0, and 20·0 mg/kg bodyweight) in ambulant patients with Duchenne muscular dystrophy aged 5–15 years with amenable deletions in DMD. Participants had a muscle biopsy before starting treatment and after 12 weekly intravenous infusions of AVI-4658. The primary study objective was to assess safety and tolerability of AVI-4658. The secondary objectives were pharmacokinetic properties and the ability of AVI-4658 to induce exon 51 skipping and dystrophin restoration by RT-PCR, immunohistochemistry, and immunoblotting. The study is registered, number NCT00844597. Findings 19 patients took part in the study. AVI-4658 was well tolerated with no drug-related serious adverse events. AVI-4658 induced exon 51 skipping in all cohorts and new dystrophin protein expression in a significant dose-dependent (p=0·0203), but variable, manner in boys from cohort 3 (dose 2 mg/kg) onwards. Seven patients responded to treatment, in whom mean dystrophin fluorescence intensity increased from 8·9% (95% CI 7·1–10·6) to 16·4% (10·8–22·0) of normal control after treatment (p=0·0287). The three patients with the greatest responses to treatment had 21%, 15%, and 55% dystrophin-positive fibres after treatment and these findings were confirmed with western blot, which showed an increase after treatment of protein levels from 2% to 18%, from 0·9% to 17%, and from 0% to 7·7% of normal muscle, respectively. The dystrophin-associated proteins α-sarcoglycan and neuronal nitric oxide synthase were also restored at the sarcolemma. Analysis of the inflammatory infiltrate indicated a reduction of cytotoxic T cells in the post-treatment muscle biopsies in the two high-dose cohorts. Interpretation The safety and biochemical efficacy that we present show the potential of AVI-4658 to become a disease-modifying drug for Duchenne muscular dystrophy. Funding UK Medical Research Council; AVI BioPharma.
Summary Background Duchenne muscular dystrophy is caused by dystrophin deficiency and muscle deterioration and preferentially affects boys. Antisense-oligonucleotide-induced exon skipping allows ...synthesis of partially functional dystrophin. We investigated the efficacy and safety of drisapersen, a 2′-O-methyl-phosphorothioate antisense oligonucleotide, given for 48 weeks. Methods In this exploratory, double-blind, placebo-controlled study we recruited male patients (≥5 years of age; time to rise from floor ≤7 s) with Duchenne muscular dystrophy from 13 specialist centres in nine countries between Sept 1, 2010, and Sept 12, 2012. By use of a computer-generated randomisation sequence, we randomly allocated patients (2:2:1:1; block size of six; no stratification) to drisapersen 6 mg/kg or placebo, each given subcutaneously and either continuously (once weekly) or intermittently (nine doses over 10 weeks). The primary endpoint was change in 6-min walk distance (6MWD) at week 25 in patients in the intention-to-treat population for whom data were available. Safety assessments included renal, hepatic, and haematological monitoring and recording of adverse events. This trial is registered with ClinicalTrials.gov , number NCT01153932. Findings We recruited 53 patients: 18 were given continuous drisapersen, 17 were given intermittent drisapersen, and 18 were given placebo (continuous and intermittent groups combined). At week 25, mean 6MWD had increased by 31·5 m (SE 9·8) from baseline for continuous drisapersen, with a mean difference in change from baseline of 35·09 m (95% CI 7·59 to 62·60; p=0·014) versus placebo. We recorded no difference in 6MWD changes from baseline between intermittent drisapersen (mean change −0·1 SE 10·3) and placebo (mean difference 3·51 m −24·34 to 31·35) at week 25. The most common adverse events in drisapersen-treated patients were injection-site reactions (14 patients given continuous drisapersen, 15 patients given intermittent drisapersen, and six given placebo) and renal events (13 for continuous drisapersen, 12 for intermittent drisapersen, and seven for placebo), most of which were subclinical proteinuria. None of the serious adverse events reported (one for continuous, two for intermittent, and two for placebo) resulted in withdrawal from the study. Interpretation Continuous drisapersen resulted in some benefit in 6MWD versus placebo at week 25. The safety findings are similar to those from previous studies. Ambulation improvements in this young population with early-stage Duchenne muscular dystrophy are encouraging but need to be confirmed in larger studies. Funding GlaxoSmithKline, Prosensa Therapeutics BV (a subsidiary of Prosensa Holding NV).
Duchenne muscular dystrophy (DMD) is a rare pediatric neuromuscular disease associated with progressive muscle degeneration and extensive care needs. Our objective was to estimate the caregiver ...burden associated with DMD. We made cross-sectional assessments of caregiver health-related quality of life (HRQL) and burden using the EuroQol EQ-5D, a Visual Analogue Scale (VAS), the SF-12 Health Survey, and the Zarit Caregiver Burden Interview (ZBI) administered online. Results were stratified by disease stage (early/late ambulatory/non-ambulatory) and caregivers’ rating of patients’ health and mental status. In total, caregivers to 770 patients participated. Mean EQ-5D utility ranged between 0.85 (95 % CI 0.82–0.88) and 0.77 (0.74–0.80) across ambulatory classes and 0.88 (0.85–0.90) and 0.57 (0.39–0.74) across caregivers’ rating of patients’ health and mental status. Mean VAS score was 0.74 (0.73–0.75), mean SF-12 Mental Health Component Summary score 44 (43–45), and mean ZBI score 29 (28–30). Anxiety and depression, recorded in up to 70 % of caregivers depending on patients’ health and mental status, was significantly associated with annual household cost burden (>$5000 vs. <$1000, odds ratio 1.76, 95 % CI 1.18–2.63) and hours of leisure time devoted to informal care per week (25–50 vs. <25 h 2.01, 1.37–2.94; >50 vs. <25 h 3.35, 2.32–4.83) (
p
< 0.007). We show that caring for a person with DMD can be associated with a substantial burden and impaired HRQL. Our findings suggest that caregivers to patients with DMD should be screened for depression and emphasize the need for a holistic approach to family mental health in the context of chronic childhood disease.
Children with Duchenne muscular dystrophy (DMD) are shorter than their healthy peers. The introduction of corticosteroid (CS) has beneficial effects on muscle function but slows growth further and is ...associated with pubertal delay. In contrast to CS usage in most children and adolescents, weaning glucocorticoid is not a key objective of management in DMD. As the outlook for these young people improves, one of the main challenges is to reduce or offset the detrimental effects of CS on growth and development. This is a review of the aetiology and prevalence of short stature and delayed puberty in DMD, a summary of the treatments available and suggestions for areas of further research.
Duchenne muscular Dystrophy (DMD) is an inherited disease caused by mutations in the dystrophin gene that disrupt the open reading frame, while in frame mutations result in Becker muscular dystrophy ...(BMD). Ullrich congenital muscular dystrophy (UCMD) is due to mutations affecting collagen VI genes. Specific muscle miRNAs (dystromirs) are potential non-invasive biomarkers for monitoring the outcome of therapeutic interventions and disease progression. We quantified miR-1, miR-133a,b, miR-206 and miR-31 in serum from patients with DMD, BMD, UCMD and healthy controls. MiR-1, miR-133a,b and miR-206 were upregulated in DMD, but unchanged in UCMD compared to controls. Milder DMD patients had higher levels of dystromirs than more severely affected patients. Patients with low forced vital capacity (FVC) values, indicating respiratory muscle weakness, had low levels of serum miR-1 and miR-133b. There was no significant difference in the level of the dystromirs in BMD compared to controls. We also assessed the effect of dystrophin restoration on the expression of the five dystromirs in serum of DMD patients treated systemically for 12 weeks with antisense oligomer eteplirsen that induces skipping of exon 51 in the dystrophin gene. The dystromirs were also analysed in muscle biopsies of DMD patients included in a single dose intramuscular eteplirsen clinical trial. Our analysis detected a trend towards normalization of these miRNA between the pre- and post-treatment samples of the systemic trial, which however failed to reach statistical significance. This could possibly be due to the small number of patients and the short duration of these clinical trials. Although longer term studies are needed to clarify the relationship between dystrophin restoration following therapeutic intervention and the level of circulating miRNAs, our results indicate that miR-1 and miR-133 can be considered as exploratory biomarkers for monitoring the progression of muscle weakness and indirectly the remaining muscle mass in DMD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Mutations that disrupt the open reading frame and prevent full translation of DMD , the gene that encodes dystrophin, underlie the fatal X-linked disease Duchenne muscular ...dystrophy. Oligonucleotides targeted to splicing elements (splice switching oligonucleotides) in DMD pre-mRNA can lead to exon skipping, restoration of the open reading frame, and the production of functional dystrophin in vitro and in vivo, which could benefit patients with this disorder. Methods We did a single-blind, placebo-controlled, dose-escalation study in patients with DMD recruited nationally, to assess the safety and biochemical efficacy of an intramuscular morpholino splice-switching oligonucleotide (AVI-4658) that skips exon 51 in dystrophin mRNA. Seven patients with Duchenne muscular dystrophy with deletions in the open reading frame of DMD that are responsive to exon 51 skipping were selected on the basis of the preservation of their extensor digitorum brevis (EDB) muscle seen on MRI and the response of cultured fibroblasts from a skin biopsy to AVI-4658. AVI-4658 was injected into the EDB muscle; the contralateral muscle received saline. Muscles were biopsied between 3 and 4 weeks after injection. The primary endpoint was the safety of AVI-4658 and the secondary endpoint was its biochemical efficacy. This trial is registered, number NCT00159250. Findings Two patients received 0·09 mg AVI-4658 in 900 μL (0·9%) saline and five patients received 0·9 mg AVI-4658 in 900 μL saline. No adverse events related to AVI-4658 administration were reported. Intramuscular injection of the higher-dose of AVI-4658 resulted in increased dystrophin expression in all treated EDB muscles, although the results of the immunostaining of EDB-treated muscle for dystrophin were not uniform. In the areas of the immunostained sections that were adjacent to the needle track through which AVI-4658 was given, 44–79% of myofibres had increased expression of dystrophin. In randomly chosen sections of treated EDB muscles, the mean intensity of dystrophin staining ranged from 22% to 32% of the mean intensity of dystrophin in healthy control muscles (mean 26·4%), and the mean intensity was 17% (range 11–21%) greater than the intensity in the contralateral saline-treated muscle (one-sample paired t test p=0·002). In the dystrophin-positive fibres, the intensity of dystrophin staining was up to 42% of that in healthy muscle. We showed expression of dystrophin at the expected molecular weight in the AVI-4658-treated muscle by immunoblot. Interpretation Intramuscular AVI-4658 was safe and induced the expression of dystrophin locally within treated muscles. This proof-of-concept study has led to an ongoing systemic clinical trial of AVI-4658 in patients with DMD. Funding UK Department of Health.
ABSTRACT
Introduction
The significance of abnormal cardiac measures in asymptomatic females who harbor dystrophin gene mutations is controversial.
Methods
Echo‐measures of ventricular function were ...compared with published norms in a cross‐sectional study of 130 (age, 39 ± 15.7 years) “carriers” of Duchenne or Becker muscular dystrophy (DMD/BMD). Correlations between cardiomyopathy (CM) and mutation, creatine kinase (CK) levels, age, and muscle symptoms were investigated.
Results
Depending on definition, CM prevalence was 3–33%. Ejection fraction (Simpson method) was < 55% in 9 (13%) and < 40% in 2 (2.9%). Eleven (8.5%) had wall motion abnormalities. Left ventricular end‐systolic dimensions were increased in 7 (5.7%) and end‐diastolic in 17 (13.9%). CM did not correlate with mutation type, DMD or BMD phenotype, CK level, muscle symptoms, or age.
Conclusions
Occult CM can be found by screening in DMD/BMD carriers. Its lack of age‐correlation suggests that not all abnormalities progress. Optimum screening schedules require a better understanding of progressive CM. Muscle Nerve 55: 810–818, 2017
The differential mechanism of action of vamorolone compared to traditional corticosteroid anti-inflammatory drugs is attributed to the loss of gene transcriptional activities associated with ...glucocorticoid response element binding and activation, potent antagonist activity for the mineralocorticoid receptor, superior membrane stabilization properties, and retention of the distinct NFκB inhibitory (anti-inflammatory) activities 3,5–7). Safety endpoints (linear growth, body mass index) are also compared with data from a 12-month trial of daily prednisone (0.75 mg/kg group) in similar-aged boys with DMD 17. Methods Ethics statement All studies had appropriate approvals by ethics committees or institutional review boards, as required by the 11 participating international academic clinical recruitment sites: (Duke University, Durham, NC, US; Alberta Children’s Hospital, Calgary, AB, Canada; Nemours Children’s Hospital, Orlando, FL, US; John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Queen Silvia Children’s Hospital, Gothenburg, Sweden; Schneider Children’s Medical Center, Tel Aviv University, Petah Tikvah, Israel; Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, VIC, Australia; The Children’s Hospital at Westmead, Sydney, NSW, Australia; University of Texas Southwestern Medical Center, Dallas, TX, US; Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL, US; University of California Davis, Davis, CA, US). ...the total duration of corticosteroid treatment was longer than 18 months for most participants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We evaluated whether whole-body dual-energy X-ray absorptiometry (DXA) measures of lean body mass can be used as biomarkers for disease progression and treatment effects in patients with Duchenne ...muscular dystrophy. This post hoc analysis utilized data from a randomized, 2-period study of domagrozumab versus placebo in 120 ambulatory boys with DMD. DXA measures of lean body mass were obtained from the whole body (excluding head), arms, legs and appendicular skeleton at baseline and every 16 weeks. Treatment effects on DXA measures for domagrozumab versus placebo were assessed at Week 49. At Week 49, domagrozumab statistically significantly increased lean body mass versus placebo in the appendicular skeleton (p = 0.050) and arms (p < 0.001). The relationship between lean body mass at Week 49 and functional endpoints at Week 97 was evaluated. Changes in lean body mass at Week 49 in all regions except arms were significantly correlated with percent change from baseline in 4-stair climb (4SC) at Week 97. DXA-derived percent lean mass at Week 49 also correlated with 4SC and North Star Ambulatory Assessment at Week 97. These data indicate that whole-body DXA measures can be used as biomarkers for treatment effects and disease progression in patients with DMD, and warrant further investigation.Trial registration: ClinicalTrials.gov, NCT02310763; registered 8 December 2014.
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