Nusinersen Improves Walking Distance and Reduces Fatigue in Later-Onset SMA

INTRODUCTION: Ambulatory individuals with spinal muscular atrophy (SMA) experience muscle weakness, gait impairments and fatigue that affect their walking ability. Improvements have been observed in motor function in children treated with nusinersen but its impact on fatigue has not been studied. METHODS: Post hoc analyses examined changes in 6-Minute Walk Test (6MWT) distance and fatigue in children and adolescents with SMA Type II and III who received their first dose of nusinersen in the phase Ib/IIa open-label CS2 study and were ambulatory during CS2 or the extension study CS12. RESULTS: Fourteen children performed the 6MWT. Median (25th, 75th percentile) distance walked increased over time by 98.0 (62.0, 135.0) meters at day 1050, while median fatigue changed by -3.8% (-19.7%, 1.4%). DISCUSSION: These results support previous studies demonstrating clinically meaningful effects of nusinersen on motor function in children and adolescents with later-onset SMA. This article is protected by copyright. All rights reserved

Melatonin attenuates the detrimental effects of UVA

Background People living in Mediterranean countries are mostly exposed to solar ultraviolet (UV) radiation that damages skin and results in photoaging which involves activation of epidermal growth factor receptor (EGFR) and downstream signal transduction through mitogen-activated protein kinases (MAPKs) in fibroblasts. Generation of reactive oxygen/nitrogen species by UV radiation is also critical for EGFR and MAPKs activation. MAPKs are responsible for activation of AP-1 subunits in the nucleus which induce matrix metalloproteinases. Melatonin, along with its metabolites, are known to be the most effective free radical scavenger and protective agent due to its ability to react with various radicals, lipophilic/hydrophilic structures. Objectives In this study, we investigated the effects of melatonin on UVA-irradiated primary human dermal fibroblasts (HDFs) by following the alteration of molecules from cell membrane to the nucleus and oxidative/nitrosative damage status of the cells in a time-dependent manner which have not been clearly elucidated yet. Methods To mimic UVA dosage in Mediterranean countries, HDFs were exposed to UVA with sub-cytotoxic dosage (20 J/cm(2)) after pretreatment with melatonin (1 mu mol/L) for 1 hour. Changes in the activation of the molecules and oxidative/nitrosative stress damage were analyzed at different time points. Results Our results clearly show that melatonin decreases UVA-induced oxidative/nitrosative stress damage in HDFs. It also suppresses phosphorylation of EGFR, activation of MAPK/AP-1 signal transduction pathway and production of matrix metalloproteinases in a time-dependent manner. Conclusion Melatonin can be used as a protective agent for skin damage against intracellular detrimental effects of relatively high dosage of UVA irradiation