| 1. |
- Campbell, C., et al.
(författare)
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Meta-analyses of ataluren randomized controlled trials in nonsense mutation Duchenne muscular dystrophy
- 2020
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Ingår i: Journal of Comparative Effectiveness Research. - : Becaris Publishing Limited. - 2042-6305 .- 2042-6313. ; 9:14
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Tidskriftsartikel (refereegranskat)abstract
- Aim:Assess the totality of efficacy evidence for ataluren in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD).Materials & methods:Data from the two completed randomized controlled trials (ClinicalTrials.gov: NCT00592553; NCT01826487) of ataluren in nmDMD were combined to examine the intent-to-treat (ITT) populations and two patient subgroups (baseline 6-min walk distance [6MWD] >= 300-<400 or <400 m). Meta-analyses examined 6MWD change from baseline to week 48.Results:Statistically significant differences in 6MWD change with ataluren versus placebo were observed across all three meta-analyses. Least-squares mean difference (95% CI): ITT (n = 342), +17.2 (0.2-34.1) m, p = 0.0473; >= 300-<400 m (n = 143), +43.9 (18.2-69.6) m, p = 0.0008; <400 m (n = 216), +27.7 (6.4-49.0) m, p = 0.0109.Conclusion:These meta-analyses support previous evidence for ataluren in slowing disease progression versus placebo in patients with nmDMD over 48 weeks. Treatment benefit was most evident in patients with a baseline 6MWD >= 300-<400 m (the ambulatory transition phase), thereby informing future trial design.
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| 2. |
- Mercuri, E., et al.
(författare)
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Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
- 2018
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 378:7, s. 625-635
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2: 1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (>= 3 points), an outcome that indicates improvement in at least two motor skills. RESULTS In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P< 0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P< 0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537.)
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| 3. |
- Del Dotto, V., et al.
(författare)
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SSBP1 mutations cause mtDNA depletion underlying a complex optic atrophy disorder
- 2020
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Ingår i: Journal of Clinical Investigation. - : American Society for Clinical Investigation. - 0021-9738 .- 1558-8238. ; 130:1, s. 108-125
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Tidskriftsartikel (refereegranskat)abstract
- Inherited optic neuropathies include complex phenotypes, mostly driven by mitochondrial dysfunction. We report an optic atrophy spectrum disorder, including retinal macular dystrophy and kidney insufficiency leading to transplantation, associated with mitochondrial DNA (mtDNA) depletion without accumulation of multiple deletions. By whole-exome sequencing, we identified mutations affecting the mitochondrial single-strand binding protein (SSBP1) in 4 families with dominant and 1 with recessive inheritance. We show that SSBP1 mutations in patient-derived fibroblasts variably affect the amount of SSBP1 protein and alter multimer formation, but not the binding to ssDNA. SSBP1 mutations impaired mtDNA, nucleoids, and 7S-DNA amounts as well as mtDNA replication, affecting replisome machinery. The variable mtDNA depletion in cells was reflected in severity of mitochondrial dysfunction, including respiratory efficiency, OXPHOS subunits, and complex amount and assembly. mtDNA depletion and cytochrome c oxidase-negative cells were found ex vivo in biopsies of affected tissues, such as kidney and skeletal muscle. Reduced efficiency of mtDNA replication was also reproduced in vitro, confirming the pathogenic mechanism. Furthermore, ssbp1 suppression in zebrafish induced signs of nephropathy and reduced optic nerve size, the latter phenotype complemented by WT mRNA but not by SSBP1 mutant transcripts. This previously unrecognized disease of mtDNA maintenance implicates SSBP1 mutations as a cause of human pathology.
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| 6. |
- Iacomino, G., et al.
(författare)
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Circulating miRNAs are associated with sleep duration in children/adolescents: Results of the I.Family Study
- 2020
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Ingår i: Experimental Physiology. - : Wiley. - 0958-0670 .- 1469-445X. ; 105:2, s. 347-356
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Tidskriftsartikel (refereegranskat)abstract
- New Findings What is the central question of this study?Are differential patterns of circulating miRNAs associated with sleep duration in normal-weight European children and adolescents? What is the main finding and its importance?Differences in the expression level of circulating miR-26b-3p and miR-485-5p are positively associated with total sleep duration in healthy normal-weight children and adolescents. It is commonly recognized that sleep is essential for children's health, and that insufficient sleep duration is associated with negative health outcomes. In humans, sleep duration and quality are influenced by genetic, environmental and social factors. Epigenetic mechanisms, likewise, regulate circadian rhythms and sleep patterns. In the present study, we aimed to identify circulating microRNAs associated with sleep duration in a subsample of normal-weight European children/adolescents (n = 111) participating in the I.Family Study. Subjects were divided into two groups based upon self-reported sleep duration, according to the recommended amount of sleep for paediatric populations. Sleep needs for children <13 years were at least 9 h per day, and for children >13 were at least 8 h per day. There were group differences (short sleepers versus normal sleepers) in circulating levels of miR-26b-3p (mean (95% CI) = 2.0 (1.3-2.7) versus 2.3 (1.9-2.7), P = 0.05) and miR-485-5p (mean (95% CI) = 0.6 (0.3-0.9) versus 0.9 (0.7 - 1.0), P < 0.001), adjusting for country of origin, age, sex, pubertal status, screen time and highest educational level of parents. Our findings show for the first time that sleep duration reflects the profile of specific circulating microRNAs in school-aged children and adolescents. It is conceivable that epigenetic modifications, mainly related to circadian rhythm control, may be modulated or interfere with sleep duration.
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| 7. |
- Iacomino, G., et al.
(författare)
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The association of circulating miR-191 and miR-375 expression levels with markers of insulin resistance in overweight children: an exploratory analysis of the I.Family Study
- 2021
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Ingår i: Genes and Nutrition. - : Springer Science and Business Media LLC. - 1555-8932 .- 1865-3499. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: In recent years, the exciting emergence of circulating miRNAs as stable, reproducible, and consistent among individuals has opened a promising research opportunity for the detection of non-invasive biomarkers. A firm connection has been established between circulating miRNAs and glycaemic as well as metabolic homeostasis, showing that levels of specific miRNAs vary under different physio-pathological conditions. Objective: In this pilot study, we investigated the expression of candidate miRNAs, hsa-miR-191-3p and hsa-miR-375, in relation to biomarkers associated with insulin sensitivity in a subgroup (n=58) of subjects participating to the European I.Family Study, a project aimed to assess the determinants of eating behaviour in children and adolescents and related health outcomes. The sample included overweight/obese children/adolescents since overweight/obesity is a known risk factor for impaired glucose homeostasis and metabolic disorders. Biological targets of candidate miRNAs were also explored in silico. Results: We observed a significant association of the two miRNAs and early changes in glycaemic homeostasis, independent of covariates including country of origin, age, BMI z-score, puberty status, highest educational level of parents, total energy intake, energy from fats, energy from carbohydrates, and energy from proteins. Conclusion: Identification of circulating miRNAs associated with insulin impairment may offer novel approaches of assessing early variations in insulin sensitivity and provide evidence about the molecular mechanisms connected to early changes in glycaemic homeostasis. Trial registration: ISRCTN, ISRCTN62310987. Retrospectively registered, http://isrctn.com/ISRCTN62310987 © 2021, The Author(s).
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| 8. |
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| 9. |
- Wang, CH, et al.
(författare)
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Consensus statement on standard of care for congenital muscular dystrophies
- 2010
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Ingår i: Journal of child neurology. - : SAGE Publications. - 1708-8283 .- 0883-0738. ; 25:12, s. 1559-1581
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Tidskriftsartikel (refereegranskat)abstract
- Congenital muscular dystrophies are a group of rare neuromuscular disorders with a wide spectrum of clinical phenotypes. Recent advances in understanding the molecular pathogenesis of congenital muscular dystrophy have enabled better diagnosis. However, medical care for patients with congenital muscular dystrophy remains very diverse. Advances in many areas of medical technology have not been adopted in clinical practice. The International Standard of Care Committee for Congenital Muscular Dystrophy was established to identify current care issues, review literature for evidence-based practice, and achieve consensus on care recommendations in 7 areas: diagnosis, neurology, pulmonology, orthopedics/rehabilitation, gastroenterology/ nutrition/speech/oral care, cardiology, and palliative care. To achieve consensus on the care recommendations, 2 separate online surveys were conducted to poll opinions from experts in the field and from congenital muscular dystrophy families. The final consensus was achieved in a 3-day workshop conducted in Brussels, Belgium, in November 2009. This consensus statement describes the care recommendations from this committee.
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