scholarly journals Nusinersen Modulates Proteomics Profiles of Cerebrospinal Fluid in Spinal Muscular Atrophy Type 1 Patients

2021 ◽  
Vol 22 (9) ◽  
pp. 4329
Author(s):  
Laura Bianchi ◽  
Maria Sframeli ◽  
Lorenza Vantaggiato ◽  
Gian Luca Vita ◽  
Annamaria Ciranni ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Disease Progression ◽  
Muscular Atrophy ◽  
Protein Pattern ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Apolipoprotein A1 ◽  
Proteomic Approach

Spinal muscular atrophy (SMA) type 1 is a severe infantile autosomal-recessive neuromuscular disorder caused by a survival motor neuron 1 gene (SMN1) mutation and characterized by progressive muscle weakness. Without supportive care, SMA type 1 is rapidly fatal. The antisense oligonucleotide nusinersen has recently improved the natural course of this disease. Here, we investigated, with a functional proteomic approach, cerebrospinal fluid (CSF) protein profiles from SMA type 1 patients who underwent nusinersen administration to clarify the biochemical response to the treatment and to monitor disease progression based on therapy. Six months after starting treatment (12 mg/5 mL × four doses of loading regimen administered at days 0, 14, 28, and 63), we observed a generalized reversion trend of the CSF protein pattern from our patient cohort to that of control donors. Notably, a marked up-regulation of apolipoprotein A1 and apolipoprotein E and a consistent variation in transthyretin proteoform occurrence were detected. Since these multifunctional proteins are critically active in biomolecular processes aberrant in SMA, i.e., synaptogenesis and neurite growth, neuronal survival and plasticity, inflammation, and oxidative stress control, their nusinersen induced modulation may support SMN improved-expression effects. Hence, these lipoproteins and transthyretin could represent valuable biomarkers to assess patient responsiveness and disease progression.

Cytochemical Characterization of Cerebrospinal Fluid Macrophage Inclusions in Pediatric Patients Receiving Intrathecal Nusinersen (SPINRAZA®) for Spinal Muscular Atrophy

2021 ◽  
pp. 1-6
Author(s):  
Kristian T. Schafernak ◽  
Jeffrey R. Jacobsen ◽  
Dulce Hernandez ◽  
Robin D. Kaye ◽  
Sylvia E. Perez
Keyword(s):  
Cerebrospinal Fluid ◽  
Spinal Muscular Atrophy ◽  
Pediatric Patients ◽  
Muscular Atrophy ◽  
Exon Skipping ◽  
Neuromuscular Disorder ◽  
Case Presentation ◽  
Smn Protein

<b><i>Introduction:</i></b> Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder caused by biallelic deletion of the <i>SMN1</i> gene. Nusinersen, an antisense oligonucleotide delivered intrathecally, binds to the pre-mRNA of <i>SMN1</i>’s pseudogene, <i>SMN2</i>, to prevent exon skipping and produce functional SMN protein to compensate for the deficiency caused by <i>SMN1</i> deletion. <b><i>Case Presentation:</i></b> We reviewed 15 cerebrospinal fluid (CSF) cytology specimens from 8 patients receiving nusinersen for SMA. Macrophages with peculiar inclusions (“nusinophages”) were seen in 8 specimens from 4 of the patients: 1 infant and 3 children with SMA type 1. This finding has only previously been reported in adults with SMA types 2 and 3 and in 2 infants with SMA type 1. <b><i>Discussion/Conclusion:</i></b> Specimens containing nusinophages had a significantly higher proportion of macrophages and lower proportion of lymphocytes than those in which nusinophages were not detected. The macrophage inclusions do not represent iron or microorganisms and instead are composed, at least in part, of glycosaminoglycans. Because CSF is a common specimen type, cytotechnologists and cytopathologists need to be aware of these inclusions, so they do not interpret them erroneously as evidence of infection or hemorrhage, especially in light of the fact that oligonucleotide therapy has been approved for a variety of conditions and is currently under investigation for intrathecal delivery in several other neurodegenerative disorders.

scholarly journals Serum creatinine is a biomarker of progressive denervation in spinal muscular atrophy

Neurology ◽  
2019 ◽  
Vol 94 (9) ◽  
pp. e921-e931 ◽  
Author(s):  
Christiano R.R. Alves ◽  
Ren Zhang ◽  
Alec J. Johnstone ◽  
Reid Garner ◽  
Pann H. Nwe ◽  
...  
Keyword(s):  
Serum Creatinine ◽  
Spinal Muscular Atrophy ◽  
Disease Severity ◽  
Lean Mass ◽  
Muscular Atrophy ◽  
Compound Muscle Action Potential ◽  
Survival Motor Neuron ◽  
Mixed Effect

ObjectiveIdentifying simple biomarkers that can predict or track disease progression in patients with spinal muscular atrophy (SMA) remains an unmet clinical need. To test the hypothesis that serum creatinine (Crn) could be a prognostic biomarker for monitoring progression of denervation in patients with SMA, we determined whether serum Crn concentration correlates with disease severity in patients with SMA.MethodsWe examined a cohort of 238 patients with SMA with 1,130 Crn observations between 2000 and 2016. Analyses were corrected for age, and 156 patients with SMA had dual-energy x-ray absorptiometry data available for correction for lean mass. We investigated the relationship between Crn and SMA type, survival motor neuron 2 (SMN2) copies, and Hammersmith Functional Motor Scale (HFMS) score as primary outcomes. In addition, we tested for associations between Crn and maximum ulnar compound muscle action potential amplitude (CMAP) and motor unit number estimation (MUNE).ResultsPatients with SMA type 3 had 2.2-fold (95% confidence interval [CI] 1.93–2.49; p < 0.0001) higher Crn levels compared to those with SMA type 1 and 1.7-fold (95% CI 1.52–1.82; p < 0.0001) higher Crn levels compared to patients with SMA type 2. Patients with SMA type 2 had 1.4-fold (95% CI 1.31–1.58; p < 0.0001) higher Crn levels than patients with SMA type 1. Patients with SMA with 4 SMN2 copies had 1.8-fold (95% CI 1.57–2.11; p < 0.0001) higher Crn levels compared to patients with SMA with 2 SMN2 copies and 1.4-fold (95% CI 1.24–1.58; p < 0.0001) higher Crn levels compared to patients with SMA with 3 SMN2 copies. Patients with SMA with 3 SMN2 copies had 1.4-fold (95% CI 1.21–1.56; p < 0.0001) higher Crn levels than patients with SMA with 2 SMN2 copies. Mixed-effect model revealed significant differences in Crn levels among walkers, sitters, and nonsitters (p < 0.0001) and positive associations between Crn and maximum CMAP (p < 0.0001) and between Crn and MUNE (p < 0.0001). After correction for lean mass, there were still significant associations between Crn and SMA type, SMN2 copies, HFMS, CMAP, and MUNE.ConclusionsThese findings indicate that decreased Crn levels reflect disease severity, suggesting that Crn is a candidate biomarker for SMA progression. We conclude that Crn measurements should be included in the routine analysis of all patients with SMA. In future studies, it will be important to determine whether Crn levels respond to molecular and gene therapies.

scholarly journals Growth patterns in children with spinal muscular atrophy

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ramona De Amicis ◽  
Giovanni Baranello ◽  
Andrea Foppiani ◽  
Alessandro Leone ◽  
Alberto Battezzati ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Severe Form ◽  
Growth Patterns ◽  
Standards Of Care ◽  
Growth Standards ◽  
Treatment Naïve

Abstract Background Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards. Results Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4–1.6) and 4.1 (2.1–6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages. Conclusions These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth.

scholarly journals Muscle regulates mTOR dependent axonal local translation in motor neurons via CTRP3 secretion: implications for a neuromuscular disorder, spinal muscular atrophy

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Wiebke A. Rehorst ◽  
Maximilian P. Thelen ◽  
Hendrik Nolte ◽  
Clara Türk ◽  
Sebahattin Cirak ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Spinal Muscular Atrophy ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Synthesis Rate ◽  
Protein Synthesis Rate ◽  
Metabolic Labeling

Abstract Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder, which causes dysfunction/loss of lower motor neurons and muscle weakness as well as atrophy. While SMA is primarily considered as a motor neuron disease, recent data suggests that survival motor neuron (SMN) deficiency in muscle causes intrinsic defects. We systematically profiled secreted proteins from control and SMN deficient muscle cells with two combined metabolic labeling methods and mass spectrometry. From the screening, we found lower levels of C1q/TNF-related protein 3 (CTRP3) in the SMA muscle secretome and confirmed that CTRP3 levels are indeed reduced in muscle tissues and serum of an SMA mouse model. We identified that CTRP3 regulates neuronal protein synthesis including SMN via mTOR pathway. Furthermore, CTRP3 enhances axonal outgrowth and protein synthesis rate, which are well-known impaired processes in SMA motor neurons. Our data revealed a new molecular mechanism by which muscles regulate the physiology of motor neurons via secreted molecules. Dysregulation of this mechanism contributes to the pathophysiology of SMA.

Clinical phenotypes and trajectories of disease progression in type 1 spinal muscular atrophy

2018 ◽  
Vol 28 (1) ◽  
pp. 24-28 ◽  
Author(s):  
Roberto De Sanctis ◽  
Marika Pane ◽  
Giorgia Coratti ◽  
Concetta Palermo ◽  
Daniela Leone ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Disease Progression ◽  
Muscular Atrophy ◽  
Clinical Phenotypes

scholarly journals Gene therapy for spinal muscular atrophy: the Qatari experience

Gene Therapy ◽  
2021 ◽  
Author(s):  
Hossamaldein Gaber Ali ◽  
Khalid Ibrahim ◽  
Mahmoud Fawzi Elsaid ◽  
Reem Babiker Mohamed ◽  
Mahmoud I. A. Abeidah ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Spinal Muscular Atrophy ◽  
Troponin I ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Progressive Muscle Weakness ◽  
Elevated Bilirubin

AbstractSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by hypotonia, progressive muscle weakness, and wasting. Onasemnogene abeparvovec (Zolgensma®) is a novel gene therapy medicine, FDA-approved in May 2019 for the treatment of SMA. This study aimed to describe Qatari experience with onasemnogene abeparvovec by reviewing the clinical outcomes of 9 SMA children (7 SMA type 1 and 2 with SMA type 2) aged 4‒23 months treated between November 2019 and July 2020. Children <2 years with 5q SMA with a bi-allelic mutation in the SMN1 gene were eligible for gene therapy. Liver function (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and total bilirubin), platelet count, coagulation profile, troponin-I levels, and motor scores (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders [CHOP INTEND]), were regularly monitored following gene therapy. All patients experienced elevated AST or ALT, two experienced high prothrombin time, and one experienced elevated bilirubin; all of these patients were asymptomatic. Furthermore, one event of vomiting after infusion was reported in one patient. Significant improvements in CHOP INTEND scores were observed following therapy. This study describes the short-term outcomes and safety of onasemnogene abeparvovec, which is well tolerated and shows promise for early efficacy.

scholarly journals Distal Spinal Muscular Atrophy: An Overlooked Etiology of Weaning Failure in Children with Respiratory Insufficiency

2018 ◽  
Vol 07 (03) ◽  
pp. 159-162 ◽  
Author(s):  
Asgar Eghbalkhah ◽  
Kamyar Kamrani ◽  
Nahid Khosroshahi ◽  
Hossein Yousefimanesh ◽  
Zahra Eskandarizadeh ◽  
...  
Keyword(s):  
Respiratory Distress ◽  
Spinal Muscular Atrophy ◽  
Motor Neurons ◽  
Respiratory Insufficiency ◽  
Muscular Atrophy ◽  
Pediatric Intensive Care ◽  
Neuromuscular Disorder ◽  
Weaning Failure ◽  
Life Threatening

AbstractSpinal muscular atrophy with respiratory distress type 1 (SMARD1) is a rare autosomal recessive neuromuscular disorder that involves the anterior horn motor neurons. It is a disease with a poor prognosis presenting with progressive distal motor weakness and respiratory insufficiency from diaphragmatic paralysis followed by distal muscle weakness before 6 months of age. With the intent to spread the awareness of this rare and life-threatening disease, we report a 2.5-month-old female infant with a subsequent diagnosis of SMARD1, who was admitted in our pediatric intensive care unit with chief complaint of progressive respiratory distress and poor feeding.

scholarly journals Combining multi-omics and drug perturbation profiles to identify novel treatments that improve disease phenotypes in spinal muscular atrophy

2019 ◽  
Author(s):  
Katharina E. Meijboom ◽  
Viola Volpato ◽  
Jimena Monzón-Sandoval ◽  
Joseph M. Hoolachan ◽  
Suzan M. Hammond ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Muscular Atrophy ◽  
Neuromuscular Disorder ◽  
Survival Motor Neuron ◽  
Muscle Pathology ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Disease Phenotypes ◽  
Parallel Data ◽  
Smn Protein

ABSTRACTSpinal muscular atrophy (SMA) is a neuromuscular disorder caused by loss of survival motor neuron (SMN) protein. While SMN restoration therapies are beneficial, they are not a cure. We aimed to identify novel treatments to alleviate muscle pathology combining transcriptomics, proteomics and perturbational datasets. This revealed potential drug candidates for repurposing in SMA. One of the lead candidates, harmine, was further investigated in cell and animal models, improving multiple disease phenotypes, including SMN expression and lifespan. Our work highlights the potential of multiple, parallel data driven approaches for development of novel treatments for use in combination with SMN restoration therapies.

Nusinersen in patients older than 7 months with spinal muscular atrophy type 1

Neurology ◽  
2018 ◽  
Vol 91 (14) ◽  
pp. e1312-e1318 ◽  
Author(s):  
Karolina Aragon-Gawinska ◽  
Andreea M. Seferian ◽  
Aurore Daron ◽  
Elena Gargaun ◽  
Carole Vuillerot ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Motor Function ◽  
Treatment Initiation ◽  
Muscular Atrophy ◽  
Neuromuscular Disorders ◽  
Survival Motor Neuron ◽  
Spinal Muscular Atrophy Type ◽  
Nutritional Data

ObjectiveTo evaluate the safety and clinical efficacy of nusinersen in patients older than 7 months with spinal muscular atrophy type 1 (SMA1).MethodsPatients with SMA1 were treated with nusinersen by intrathecal injections as a part of the Expanded Access Program (EAP; NCT02865109). We evaluated patients before treatment initiation (M0) and at 2 months (M2) and 6 months (M6) after treatment initiation. Survival, respiratory, and nutritional data were collected. Motor function was assessed with the modified Hammersmith Infant Neurologic Examination Part 2 (HINE-2) and physiotherapist scales adjusted to patient age (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and the Motor Function Measure 20 or 32).ResultsWe treated 33 children ranging in age from 8.3 to 113.1 months between December 2016 and May 2017. All patients were alive and were continuing treatment at M6. Median progress on the modified HINE-2 score was 1.5 points after 6 months of treatment (p < 0.001). The need for respiratory support significantly increased over time. There were no statistically significant differences between patients presenting with 2 and those presenting with 3 copies of the survival motor neuron 2 (SMN2) gene.ConclusionsOur results are in line with the phase 3 study for nusinersen in patients with SMA1 treated before 7 months of age and indicate that patients benefit from nusinersen even at a later stage of the disease.ClinicalTrials.gov identifier:NCT02865109.Classification of evidenceThis study provides Class IV evidence that for patients with SMA1 who are older than 7 months, nusinersen is beneficial.

Cervical puncture to deliver nusinersen in patients with spinal muscular atrophy

Neurology ◽  
2018 ◽  
Vol 91 (7) ◽  
pp. e620-e624 ◽  
Author(s):  
Aravindhan Veerapandiyan ◽  
Ria Pal ◽  
Stephen D'Ambrosio ◽  
Iris Young ◽  
Katy Eichinger ◽  
...  
Keyword(s):  
Spinal Muscular Atrophy ◽  
Spinal Fusion ◽  
Tissue Concentration ◽  
Muscular Atrophy ◽  
Retrospective Chart Review ◽  
Neuromuscular Disorder ◽  
Spinal Cord Tissue ◽  
Posterior Aspect ◽  
Feasible Alternative

ObjectiveTo report our experience delivering intrathecal nusinersen through cervical puncture in patients with spinal muscular atrophy (SMA) with no lumbar access.BackgroundSMA is a neuromuscular disorder characterized by profound muscle weakness, atrophy, and paralysis due to degeneration of the anterior horn cells. Nusinersen, the first Food and Drug Administration–approved treatment for SMA, is administered intrathecally via lumbar puncture; however, many patients with SMA have scoliosis or solid spinal fusion with hardware that makes lumbar access impossible. Studies in primates have demonstrated better spinal cord tissue concentration with intrathecal injections than with intracerebral ventricular injections. Therefore we have used C1/C2 puncture as an alternative to administer nusinersen.MethodRetrospective chart review.ResultsIntrathecal nusinersen via cervical puncture was given to 3 patients who had thoracic and lumbosacral spinal fusion: a 12-year-old girl with type 1 SMA and 2 17-year-old girls with type 2 SMA. Cervical puncture was performed without deep sedation under fluoroscopic guidance using a 25-G or a 24-G Whitacre needle in the posterior aspect of C1-C2 interspace and full dose of nusinersen (12 mg/5 mL) was injected after visualizing free CSF flow. Patients completed their 4 loading doses and first maintenance dose of nusinersen, and 15 procedures were successful and well-tolerated.ConclusionCervical puncture is a feasible alternative delivery route to administer intrathecal nusinersen in patients with longstanding SMA and spine anatomy precluding lumbar access when done by providers with expertise in this procedure.

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