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 The aim of our longitudinal multicentric study was to establish the changes on the 6 min walk test (6MWT) in ambulant SMA type III children and adults over a 12 month period. Thirty-eight ...ambulant type III patients performed the 6MWT at baseline and 12 months after baseline. The distance covered in 6 min ranged between 75 and 510 m (mean 294.91, SD 127) at baseline and between 50 and 611 m (mean 293.41 m, SD 141) at 12 months. The mean change in distance between baseline and 12 months was −1.46 (SD 50.1; range: −183 to 131.8 m). The changes were not correlated with age or baseline values ( p > .05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30 m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients.
The aim of our longitudinal multicentric study was to establish the changes on the 6min walk test (6MWT) in ambulant SMA type III children and adults over a 12month period. Thirty-eight ambulant type ...III patients performed the 6MWT at baseline and 12months after baseline. The distance covered in 6min ranged between 75 and 510m (mean 294.91, SD 127) at baseline and between 50 and 611m (mean 293.41m, SD 141) at 12months. The mean change in distance between baseline and 12months was −1.46 (SD 50.1; range: −183 to 131.8m). The changes were not correlated with age or baseline values (p>.05) even though younger patients reaching puberty, had a relatively higher risk of showing deterioration of more than 30m compared to older patients. Our findings provide the first longitudinal data using the 6MWT in ambulant SMA patients.
Here we present the high-resolution continuous flow analysis (CFA) data from the top 479 m of the East Greenland Ice coring Project (EGRIP) ice core covering the past 3.8 kyr. The data consist of 1 ...mm depth-resolution profiles of calcium, sodium, ammonium, nitrate, and electrolytic conductivity as well as decadal averages of these profiles. The nominally 1 mm data represent an oversampling of the record as the true resolution is limited by the analytical setup to approximately 1 cm. Alongside the data we provide a description of the measurement setup, procedures, the relevant references for the specific methods as well as an assessment of the precision of the measurements, the sample-to-depth assignment, and the depth and temporal resolution of the data set. The error in absolute depth assignment of the data may be on the order of 2 cm; however, relative depth offsets between the records of the individual species are only on the order of 1 mm. The presented data have sub-annual resolution over the entire depth range and have already formed part of the data for an annually layer-counted timescale for the EGRIP ice core used to improve and revise the multi-core Greenland ice-core chronology (GICC05) to a new version, GICC21 (Sinnl et al., 2022). The data are available in full 1 mm resolution and decadal averages on PANGAEA (https://doi.org/10.1594/PANGAEA.945293, Erhardt et al., 2022b).
Abstract Cognitive abilities have been extensively studied in children and adults with Duchenne muscular dystrophy (DMD) but less has been reported on younger children. This is not surprising as the ...diagnosis of DMD remains at a mean age of 4 and 6 months. The aim of this study was to assess neurodevelopmental abilities before the age of 4 years in a cohort of DMD patients in whom early diagnosis was possible because of incidental raised creatine kinase levels, family history or neonatal screenings. Sixty-six children with a diagnosis of DMD of age between 7 and 43 months (mean 27 months) were included in the study. All children were assessed using the Griffiths Mental Development Scales, establishing both total scores and subscores for each of the subscales. Thirty-six of the 66 children had a developmental quotient (DQ) > 85, 21 had a DQ between 70 and 84 and 9 below 70. The mean total DQ was 86 (SD 16.07) and the mean scores for each subscale were as follows: (A) locomotor: 79 (19.47), (B) personal social: 91 (18.48), (C) hearing and speech: 85 (23.59), (D) eye hand coordination: 87 (17.20), (E) performance: 88 (18.40), (F) practical reasoning: 95 (16.08). (Scale F only for patients older than 2 years.) Details of mutations were available in 58 of the 66 children included. Low DQ were found in five of the 26 (18.5 %) patients with mutations before exon 44, in 15 of the 29 with mutations between 44 and 55 (51.7 %) and in all three with mutations in the exons beyond exon 55. it Conclusions: The DQ found in our cohort was on average one SD below a DQ of 100 with approximately 45% of the children having a DQ below 85. The locomotor scale had the lowest scores but even when we excluded the locomotor scale, a DQ below 85 was found in 28 patients (43%).
ABSTRACT
Glucocorticoids (GCs) exert via glucocorticoid receptors (GRs) potent anti‐inflammatory and immunosuppressive effects. Emerging evidence indicates that an inflammatory process is involved in ...dopaminergic nigro‐striatal neuronal loss in Parkinson's disease. We here report that the GR deficiency of transgenic (Tg) mice expressing GR antisense RNA from early embryonic life has a dramatic impact in “programming” the vulnerability of dopaminergic neurons to 1‐ methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). The GR deficiency of Tg mice exacerbates MPTP‐induced toxicity to dopaminergic neurons, as revealed by both severe loss of tyrosine hydroxylase positive nigral neurons and sharp decreases in striatal levels of dopamine and its metabolites. In addition, the late increase in dopamine oxidative metabolism and ascorbic acid oxidative status in GR‐deficient mice was far greater than in wild‐type (Wt) mice. Inducible nitric oxide synthase (iNOS) was sharply increased in activated astrocytes, macrophages/microglia of GR‐deficient as compared with Wt mice. Moreover, GR‐deficient microglia produced three‐ to fourfold higher nitrite levels than Wt mice; these increases preceded the loss of dopaminergic function and were resistant to GR the inhibitory effect of GC, pointing to peroxynitrites as candidate neurotoxic effectors. The iNOS inhibitor N6‐(1‐ iminoethyl)‐L‐lysine normalized vulnerability of Tg mice, thus establishing a novel link between genetic impairment of GR function and vulnerability to MPTP.
Abstract The congenital myopathies are a group of inherited neuromuscular disorders mainly defined on the basis of characteristic histopathological features. We analysed 66 patients assessed at a ...single centre over a 5 year period. Of the 54 patients where muscle biopsy was available, 29 (54%) had a core myopathy (Central Core Disease, Multi-minicore Disease), 9 (17%) had Nemaline Myopathy, 7 (13%) had Myotubular/Centronuclear Myopathy, 2 (4%) had Congenital Fibre Type Disproportion, 6 (11%) had isolated type 1 predominance and 1 (2%) had a mixed Core–Rod Myopathy. Of the 44 patients with a genetic diagnosis, RYR1 was mutated in 26 (59%), ACTA1 in 7 (16%), SEPN1 in 7 (16%), MTM1 in 2 (5%), NEB in 1 (2%) and TPM3 in 1 (2%). Clinically, 77% of patients older than 18 months could walk independently. 35% of all patients required ventilatory support and/or enteral feeding. Clinical course was stable or improved in 57/66 (86%) patients, whilst 4 (6%) got worse and 5 (8%) died. These findings indicate that core myopathies are the most common form of congenital myopathies and that more than half can be attributed to RYR1 mutations. The underlying genetic defect remains to be identified in 1/3 of congenital myopathies cases.
Bidirectional communication between the neuroendocrine and immune systems plays a pivotal role in health and disease. Signals generated by the hypothalamic–pituitary–gonadal (HPG) axis (i.e. ...luteinizing hormone-releasing hormone, LHRH, and sex steroids) are major players coordinating the development immune system function. Conversely, products generated by immune system activation exert powerful and longlasting effects on HPG axis activity. In the central nervous system (CNS), one chief neuroendocrine-immune (NIE) compartment is represented by the astroglial cell population and its mediators. Of special interest, the major supporting cells of the brain and the thymus, astrocytes and thymic epithelial cells, share a similar origin and a similar set of peptides, transmitters, hormones and cytokines functioning as paracrine/autocrine regulators. This may explain some fundamental analogies in LHRH regulation of both cell types during ontogeny and in adult life. Hence, the neuropeptide LHRH significantly modulates astrocyte and thymic cell development and function. Here we focus this work on LHRH neuron–glial signaling cascades which dictate major changes during LHRH neuronal differentiation and growth as well as in response to hormonal manipulations and pro-inflammatory challenges. The interplay between LHRH, growth factors, estrogens and pro-inflammatory mediators will be discussed, and the potential physiopathological implications of these findings summarized. The overall study highlights the plasticity of this intersystem cross-talk and emphasize neuron–glial interactions as a key regulatory level of neuroendocrine axes activity.
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