Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this ...STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.
STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes vg/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).
From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 67% of 33), upper respiratory infection (11 33%), and increased alanine aminotransferase (nine 27%). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.
STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.
Novartis Gene Therapies.
Abstract We present a multi-epoch, multi-observatory X-ray analysis for 2FHL J1745.1–3035, a newly discovered very high-energy Galactic source detected by the Fermi Large Area Telescope (LAT) located ...in close proximity to the Galactic Center ( l = 358.°5319; b = −0.°7760). The source shows a very hard γ -ray photon index above 50 GeV, Γ γ = 1.2 ± 0.4, and is found to be a TeV emitter by the Fermi–LAT. We conduct a joint XMM-Newton, Chandra, and NuSTAR observing campaign, combining archival XMM-Newton observations, to study the X-ray spectral properties of 2FHL J1745.1–3035 over a time span of over 20 yr. The joint X-ray spectrum is best fitted as a broken-power-law model with break energy E b ∼ 7 keV: the source is very hard at energies below 10 keV, with Γ 1 ∼ 0.6, and significantly softer in the higher energy range measured by NuSTAR with Γ 2 ∼ 1.9. We also perform a spatially resolved X-ray analysis with Chandra, finding evidence for marginal extension (up to an angular size r ∼ 5″), a result that supports a compact pulsar wind nebula scenario. Based on the X-ray and γ -ray properties, 2FHL J1745.1–3035 is a powerful pulsar wind nebula candidate. Given its nature as an extreme TeV emitter, further supported by the detection of a coincident TeV extended source HESS J1745-303, 2FHL J1745.1–3035 is an ideal candidate for a follow up with the upcoming Cherenkov Telescope Array.
The analysis and combination of data from different gamma-ray instruments involves the use of collaboration proprietary software and case-by-case methods. The effort of defining a common data format ...for high-level data, namely event lists and instrument response functions (IRFs), has recently started for very-high-energy gamma-ray instruments, driven by the upcoming Cherenkov Telescope Array (CTA). In this work we implemented this prototypical data format for a small set of MAGIC, VERITAS, FACT, and H.E.S.S. Crab nebula observations, and we analyzed them with the open-source gammapy software package. By combining data from Fermi-LAT, and from four of the currently operating imaging atmospheric Cherenkov telescopes, we produced a joint maximum likelihood fit of the Crab nebula spectrum. Aspects of the statistical errors and the evaluation of systematic uncertainty are also commented upon, along with the release format of spectral measurements. The results presented in this work are obtained using open-access on-line assets that allow for a long-term reproducibility of the results.
Aims. We investigate the nature of the accelerated particles responsible for the production of the gamma-ray emission observed from the middle-aged supernova remnant (SNR) HB 21. Methods. We present ...the analysis of more than nine years of Fermi LAT data from the SNR HB 21. We performed morphological and spectral analysis of the SNR by means of a three-dimensional binned likelihood analysis. To assess the intrinsic properties of the parent particle models, we fit the obtained gamma-ray spectral energy distribution of the SNR by both hadronic- and leptonic-induced gamma-ray spectrum. Results. We observe an extended emission positionally in agreement with the SNR HB 21. The bulk of this gamma-ray emission is detected from the remnant; photons up to ~10 GeV show clear evidence of curvature at the lower energies. The remnant is characterized by an extension of 0°.83, that is, 30% smaller than claimed in previous studies. The increased statistics allowed us also to resolve a point-like source at the edge of the remnant, in proximity to a molecular cloud of the Cyg OB7 complex. In the southern part of the remnant, a hint of an additional gamma-ray excess in correspondence to shocked molecular clouds is observed. Conclusions. The spectral energy distribution of the SNR shows evidence of a break around 400 MeV, which can be properly fitted within both the hadronic and leptonic scenario. The pion-decay mechanism reproduces well the gamma rays, postulating a proton spectrum with a slope ~2.5 and with a steepening around tens of GeV, which could be explained by the energy-dependent escape of particles from the remnant. In the leptonic scenario the electron spectrum within the SNR matches closely the locally measured spectrum. This remarkable and novel result shows that SNR HB 21 could be a direct contributor to the population of Galactic electrons. In the leptonic scenario, we find that the local electron spectrum with a break around 2 GeV, closely evokes the best-fitting parental spectrum within this SNR. If such a scenario is confirmed, this would indicate that the SNR might be a source of Galactic background electrons.
Spinal muscular atrophy (SMA) is a rare autosomal-recessive neurodegenerative disorder caused by mutations in survival motor neuron 1 (SMN1) gene, and consequent loss of function of SMN protein, ...which results in progressive loss of lower motor neurons, and muscular wasting. Antisense oligonucleotide (ASO) nusinersen (SpinrazaR) modulates the pre-mRNA splicing of the SMN2 gene, allowing rebalance of biologically active SMN. It is administered intrathecally via lumbar puncture after removing an equal amount of cerebrospinal fluid (CSF). Its effect was proven beneficial and approved since 2017 for SMA treatment. Given the direct effect of nusinersen on RNA metabolism, the aim of this project was to evaluate cell-free RNA (cfRNA) in CSF of SMA patients under ASOs treatment for biomarker discovery. By RNA-sequencing approach, RNA obtained from CSF of pediatric SMA type 2 and 3 patients was processed after 6 months of nusinersen treatment, at fifth intrathecal injection (T6), and compared to baseline (T0). We observed the deregulation of cfRNAs in patients at T6 and we were able to classify these RNAs into disease specific, treatment specific and treatment dependent. Moreover, we subdivided patients into "homogeneous" and "heterogeneous" according to their gene expression pattern. The "heterogeneous" group showed peculiar activation of genes coding for ribosomal components, meaning that in these patients a different molecular effect of nusinersen is observable, even if this specific molecular response was not referable to a clinical pattern. This study provides preliminary insights into modulation of gene expression dependent on nusinersen treatment and lays the foundation for biomarkers discovery.
ABSTRACT
The Cherenkov Telescope Array (CTA) will be the next generation instrument for the very high energy gamma-ray astrophysics domain. With its enhanced sensitivity in comparison with the ...current facilities, CTA is expected to shed light on a varied population of sources. In particular, we will achieve a deeper knowledge of the Crab nebula and pulsar, which are the best characterized pulsar wind nebula and rotation powered pulsar, respectively. We aim at studying the capabilities of CTA regarding these objects through simulations, using the main tools currently in development for the CTA future data analysis: gammapy and ctools. We conclude that, even using conservative Instrument Response Functions, CTA will be able to resolve many uncertainties regarding the spectrum and morphology of the pulsar and its nebula. The large energy range covered by CTA will allow us to disentangle the nebula spectral shape among different hypotheses, corresponding to different underlying emitting mechanisms. In addition, resolving internal structures (smaller than ∼0.02° in size) in the nebula and unveiling their location, would provide crucial information about the propagation of particles in the magnetized medium. We used a theoretical asymmetric model to characterize the morphology of the nebula and we showed that if predictions of such morphology exist, for instance as a result of hydrodynamical or magneto-hydrodynamical simulations, it can be directly compared with CTA results. We also tested the capability of CTA to detect periodic radiation from the Crab pulsar obtaining a precise measurement of different light curves shapes.
We have studied the wisps to the north-west of the Crab pulsar as part of a multiwavelength campaign in the visible and in X-rays. Optical observations were obtained using the Nordic Optical ...Telescope in La Palma and X-ray observations were made with the Chandra X-ray Observatory. The observing campaign took place from 2010 October until 2012 September. About once per year we observe wisps forming and peeling off from (or near) the region commonly associated with the termination shock of the pulsar wind. We find that the exact locations of the north-western wisps in the optical and in X-rays are similar but not coincident, with X-ray wisps preferentially located closer to the pulsar. This suggests that the optical and X-ray wisps are not produced by the same particle distribution. Our measurements and their implications are interpreted in terms of a Doppler-boosted ring model that has its origin in magnetohydrodynamic (MHD) modelling. While the Doppler boosting factors inferred from the X-ray wisps are consistent with current MHD simulations of pulsar wind nebulae, the optical boosting factors are not, and typically exceed values from MHD simulations by about a factor of 3.
ABSTRACT
Since 2009, several rapid and bright flares have been observed at high energies (>100 MeV) from the direction of the Crab nebula. Several hypotheses have been put forward to explain this ...phenomenon, but the origin is still unclear. The detection of counterparts at higher energies with the next generation of Cherenkov telescopes will be determinant to constrain the underlying emission mechanisms. We aim at studying the capability of the Cherenkov Telescope Array (CTA) to explore the physics behind the flares, by performing simulations of the Crab nebula spectral energy distribution, both in flaring and steady state, for different parameters related to the physical conditions in the nebula. In particular, we explore the data recorded by Fermi during two particular flares that occurred in 2011 and 2013. The expected GeV and TeV gamma-ray emission is derived using different radiation models. The resulting emission is convoluted with the CTA response and tested for detection, obtaining an exclusion region for the space of parameters that rule the different flare emission models. Our simulations show different scenarios that may be favourable for achieving the detection of the flares in Crab with CTA, in different regimes of energy. In particular, we find that observations with low sub-100 GeV energy threshold telescopes could provide the most model-constraining results.
Context. Vela X is a pulsar wind nebula in which two relativistic particle populations with distinct spatial and spectral distributions dominate the emission at different wavelengths. An extended 2° ...× 3° nebula is seen in radio and GeV gamma rays. An elongated cocoon prevails in X-rays and TeV gamma rays. Aims. We use ~9.5 yr of data from the Fermi Large Area Telescope (LAT) to disentangle gamma-ray emission from the two components in the energy range from 10 GeV to 2 TeV, bridging the gap between previous measurements at GeV and TeV energies. Methods. We determine the morphology of emission associated to Vela X separately at energies <100 and >100 GeV, and compare it to the morphology seen at other wavelengths. Then, we derive the spectral energy distribution of the two gamma-ray components over the full energy range. Results. The best overall fit to the LAT data is provided by the combination of the two components derived at energies <100 and >100 GeV. The first component has a soft spectrum, spectral index 2.19 ± 0.16−0.22+0.05 $2.19\pm0.16^{+0.05}_{-0.22}$ 2.19±0.16−0.22+0.05 , and extends over a region of radius 1.°36±0.°04, consistent with the size of the radio nebula. The second component has a harder spectrum, spectral index 0.9 ± 0.3−0.1+0.3 $0.9\pm0.3^{+0.3}_{-0.1}$ 0.9±0.3−0.1+0.3 , and is concentrated over an area of radius 0.°63±0.°03, coincident with the X-ray cocoon that had already been established as accounting for the bulk of the emission at TeV energies. Conclusions. The spectrum measured for the low-energy component corroborates previous evidence for a roll-over of the electron spectrum in the extended radio nebula at energies of a few tens of GeV possibly due to diffusive escape. The high-energy component has a very hard spectrum: if the emission is produced by electrons with a power-law spectrum, the electrons must be uncooled, and there is a hint that their spectrum may be harder than predictions by standard models of Fermi acceleration at relativistic shocks.
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