Safety, tolerability and pharmacokinetics of eteplirsen in young boys aged 6-48 months with Duchenne muscular dystrophy amenable to exon 51 skipping

Eteplirsen is FDA-approved for the treatment of Duchenne muscular dystrophy (DMD) in exon 51 skip-amenable patients. Previous studies in boys > 4 years of age indicate eteplirsen is well tolerated and attenuates pulmonary and ambulatory decline compared with matched natural history cohorts. Here the safety, tolerability and pharmacokinetics of eteplirsen in boys aged 6–48 months is evaluated. In this open-label, multicenter, dose-escalation study (NCT03218995), boys with a confirmed mutation of the DMD gene amenable to exon 51 skipping (Cohort 1: aged 24–48 months, n = 9; Cohort 2: aged 6 to 4 years of age. These data support the safety and tolerability of eteplirsen at the approved 30-mg/kg dose in boys as young as 6 months old

Cholesterol metabolism is a potential therapeutic target in Duchenne muscular dystrophy

Background: Duchenne muscular dystrophy (DMD) is a lethal muscle disease detected in approximately 1:5000 male births. DMD is caused by mutations in the DMD gene, encoding a critical protein that links the cytoskeleton and the extracellular matrix in skeletal and cardiac muscles. The primary consequence of the disrupted link between the extracellular matrix and the myofibre actin cytoskeleton is thought to involve sarcolemma destabilization, perturbation of Ca homeostasis, activation of proteases, mitochondrial damage, and tissue degeneration. A recently emphasized secondary aspect of the dystrophic process is a progressive metabolic change of the dystrophic tissue; however, the mechanism and nature of the metabolic dysregulation are yet poorly understood. In this study, we characterized a molecular mechanism of metabolic perturbation in DMD. Methods: We sequenced plasma miRNA in a DMD cohort, comprising 54 DMD patients treated or not by glucocorticoid, compared with 27 healthy controls, in three groups of the ages of 4–8, 8–12, and 12–20 years. We developed an original approach for the biological interpretation of miRNA dysregulation and produced a novel hypothesis concerning metabolic perturbation in DMD. We used the mdx mouse model for DMD for the investigation of this hypothesis. Results: We identified 96 dysregulated miRNAs (adjusted P-value <0.1), of which 74 were up-regulated and 22 were down-regulated in DMD. We confirmed the dysregulation in DMD of Dystro-miRs, Cardio-miRs, and a large number of the DLK1-DIO3 miRNAs. We also identified numerous dysregulated miRNAs yet unreported in DMD. Bioinformatics analysis of both target and host genes for dysregulated miRNAs predicted that lipid metabolism might be a critical metabolic perturbation in DMD. Investigation of skeletal muscles of the mdx mouse uncovered dysregulation of transcription factors of cholesterol and fatty acid metabolism (SREBP-1 and SREBP-2), perturbation of the mevalonate pathway, and the accumulation of cholesterol in the dystrophic muscles. Elevated cholesterol level was also found in muscle biopsies of DMD patients. Treatment of mdx mice with Simvastatin, a cholesterol-reducing agent, normalized these perturbations and partially restored the dystrophic parameters. Conclusions: This investigation supports that cholesterol metabolism and the mevalonate pathway are potential therapeutic targets in DMD. 2

Metal-induced malformations in early Palaeozoic plankton are harbingers of mass extinction

Glacial episodes have been linked to Ordovician–Silurian extinction events, but cooling itself may not be solely responsible for these extinctions. Teratological (malformed) assemblages of fossil plankton that correlate precisely with the extinction events can help identify alternate drivers of extinction. Here we show that metal poisoning may have caused these aberrant morphologies during a late Silurian (Pridoli) event. Malformations coincide with a dramatic increase of metals (Fe, Mo, Pb, Mn and As) in the fossils and their host rocks. Metallic toxins are known to cause a teratological response in modern organisms, which is now routinely used as a proxy to assess oceanic metal contamination. Similarly, our study identifies metal-induced teratology as a deep-time, palaeobiological monitor of palaeo-ocean chemistry. The redox-sensitive character of enriched metals supports emerging ‘oceanic anoxic event’ models. Our data suggest that spreading anoxia and redox cycling of harmful metals was a contributing kill mechanism during these devastating Ordovician–Silurian palaeobiological events

Prognostic factors and treatment-effect modifiers in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a rare, progressive neuromuscular disease characterized by loss of motor neurons and muscle atrophy. Untreated infants with Type 1 SMA do not achieve major motor milestones, and death from respiratory failure typically occurs before 2 years. Individuals with Types 2 and 3 SMA exhibit milder phenotypes and have better functional and survival outcomes. Herein, a systematic literature review was conducted to identify factors that influence the prognosis of Types 1, 2 and 3 SMA. In untreated infants with Type 1 SMA, absence of symptoms at birth, a later symptom onset and a higher survival of motor neuron 2 (SMN2) copy number are all associated with increased survival. Disease duration, age at treatment initiation and, to a lesser extent, baseline function were identified as potential treatment-modifying factors for survival, emphasizing that early treatment with disease-modifying therapies (DMT) is essential in Type 1 SMA. In patients with Types 2 and 3 SMA, factors considered prognostic of changes in motor function were SMN2 copy number, age and ambulatory status. Individuals aged 6-15 years were particularly vulnerable to developing complications (scoliosis and progressive joint contractures) which negatively influence functional outcomes and may also affect the therapeutic response in patients. Age at the time of treatment initiation emerged as a treatment-effect modifier on the outcome of DMTs. Factors identified in this review should be considered prior to designing or analyzing studies in an SMA population, conducting population matching or summarizing results from different studies on the treatments for SMA

Measurements of hydrogen cyanide (HCN) and acetylene (C2H2) from the Infrared Atmospheric Sounding Interferometer (IASI)

Hydrogen cyanide (HCN) and acetylene (C2H2) are ubiquitous atmospheric trace gases with medium lifetime, which are frequently used as indicators of combustion sources and as tracers for atmospheric transport and chemistry. Because of their weak infrared absorption, overlapped by the CO2 Q branch near 720 cm−1, nadir sounders have up to now failed to measure these gases routinely. Taking into account CO2 line mixing, we provide for the first time extensive measurements of HCN and C2H2 total columns at Reunion Island (21° S, 55° E) and Jungfraujoch (46° N, 8° E) in 2009–2010 using observations from the Infrared Atmospheric Sounding Interferometer (IASI). A first order comparison with local ground-based Fourier transform InfraRed (FTIR) measurements has been carried out allowing tests of seasonal consistency which is reasonably captured, except for HCN at Jungfraujoch. The IASI data shows a greater tendency to high C2H2 values. We also examine a nonspecific biomass burning plume over austral Africa and show that the emission ratios with respect to CO agree with previously reported values

An In Vivo Platform for Tumor Biomarker Assessment

Tumor biomarkers provide a quantitative tool for following tumor progression and response to therapy. However, investigations of clinically useful tumor biomarkers are time-consuming, costly, and limited by patient and tumor heterogeneity. In addition, assessment of biomarkers as indicators of therapy response is confounded by the concomitant use of multiple therapeutic interventions. Herein we report our use of a clinically relevant orthotopic animal model of malignant pleural mesothelioma for investigating tumor biomarkers. Utilizing multi-modality imaging with correlative histopathology, we demonstrate the utility and accuracy of the mouse model in investigating tumor biomarkers – serum soluble mesothelin-related peptide (SMRP) and osteopontin (OPN). This model revealed percentage change in SMRP level to be an accurate biomarker of tumor progression and therapeutic response – a finding consistent with recent clinical studies. This in vivo platform demonstrates the advantages of a validated mouse model for the timely and cost-effective acceleration of human biomarker translational research

Upper limb disease evolution in exon 53 skipping eligible patients with Duchenne muscular dystrophy

Objective: To understand the natural disease upper limb progression over 3 years of ambulatory and non-ambulatory patients with Duchenne muscular dystrophy (DMD) using functional assessments and quantitative magnetic resonance imaging (MRI) and to exploratively identify prognostic factors. Methods: Forty boys with DMD (22 non-ambulatory and 18 ambulatory) with deletions in dystrophin that make them eligible for exon 53-skipping therapy were included. Clinical assessments, including Brooke score, motor function measure (MFM), hand grip and key pinch strength, and upper limb distal coordination and endurance (MoviPlate), were performed every 6 months and quantitative MRI of fat fraction (FF) and lean muscle cross sectional area (flexor and extensor muscles) were performed yearly. Results: In the whole population, there were strong nonlinear correlations between outcome measures. In non-ambulatory patients, annual changes over the course of 3 years were detected with high sensitivity standard response mean (|SRM| ≥0.8) for quantitative MRI-based FF, hand grip and key pinch, and MFM. Boys who presented with a FF27% were able to bring a glass to their mouth and retained this ability in the following 3 years. Ambulatory patients with grip strength >35% of predicted value and FF <10% retained ambulation 3 years later. Interpretation: We demonstrate that continuous decline in upper limb strength, function, and MRI measured muscle structure can be reliably measured in ambulatory and non-ambulatory boys with DMD with high SRM and strong correlations between outcomes. Our results suggest that a combination of grip strength and FF can be used to predict important motor milestones

Combination disease-modifying treatment in spinal muscular atrophy: A proposed classification

We sought to devise a rational, systematic approach for defining/grouping survival motor neuron-targeted disease-modifying treatment (DMT) scenarios. The proposed classification is primarily based on a two-part differentiation: initial DMT, and persistence/discontinuation of subsequent DMT(s). Treatment categories were identified: monotherapy add-on, transient add-on, combination with onasemnogene abeparvovec, bridging to onasemnogene abeparvovec, and switching to onasemnogene abeparvovec. We validated this approach by applying the classification to the 443 patients currently in the RESTORE registry and explored the demographics of these different groups of patients. This work forms the basis to explore the safety and efficacy profile of the different combinations of DMT in SMA