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https://www.readbyqxmd.com/read/27911332/type-0-spinal-muscular-atrophy-further%C3%A2-delineation-of-prenatal-and%C3%A2-postnatal-features-in-16-patients
#1
Sarah Grotto, Jean-Marie Cuisset, Stéphane Marret, Séverine Drunat, Patricia Faure, Séverine Audebert-Bellanger, Isabelle Desguerre, Vincent Flurin, Anne-Gaëlle Grebille, Anne-Marie Guerrot, Hubert Journel, Gilles Morin, Ghislaine Plessis, Sylvain Renolleau, Joëlle Roume, Brigitte Simon-Bouy, Renaud Touraine, Marjolaine Willems, Thierry Frébourg, Eric Verspyck, Pascale Saugier-Veber
BACKGROUND: Spinal muscular atrophy (SMA) is caused by homozygous inactivation of the SMN1 gene. The SMN2 copy number modulates the severity of SMA. The 0SMN1/1SMN2 genotype, the most severe genotype compatible with life, is expected to be associated with the most severe form of the disease, called type 0 SMA, defined by prenatal onset. OBJECTIVE: The aim of the study was to review clinical features and prenatal manifestations in this rare SMA subtype. METHODS: SMA patients with the 0SMN1/1SMN2 genotype were retrospectively collected using the UMD-SMN1 France database...
November 29, 2016: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/27907033/normalization-of-patient-identified-plasma-biomarkers-in-smn%C3%AE-7-mice-following-postnatal-smn-restoration
#2
W David Arnold, Sandra Duque, Chitra C Iyer, Phillip Zaworski, Vicki L McGovern, Shannon J Taylor, Katharine M von Herrmann, Dione T Kobayashi, Karen S Chen, Stephen J Kolb, Sergey V Paushkin, Arthur H M Burghes
INTRODUCTION AND OBJECTIVE: Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disorder. SMA is caused by homozygous loss of the SMN1 gene and retention of the SMN2 gene resulting in reduced levels of full length SMN protein that are insufficient for motor neuron function. Various treatments that restore levels of SMN are currently in clinical trials and biomarkers are needed to determine the response to treatment. Here, we sought to investigate in SMA mice a set of plasma analytes, previously identified in patients with SMA to correlate with motor function...
2016: PloS One
https://www.readbyqxmd.com/read/27893852/a-comparative-study-of-smn-protein-and-mrna-in-blood-and-fibroblasts-in-patients-with-spinal-muscular-atrophy-and-healthy-controls
#3
Renske I Wadman, Marloes Stam, Marc D Jansen, Yana van der Weegen, Camiel A Wijngaarde, Oliver Harschnitz, Peter Sodaar, Kees P J Braun, Dennis Dooijes, Henny H Lemmink, Leonard H van den Berg, W Ludo van der Pol
BACKGROUND: Clinical trials to test safety and efficacy of drugs for patients with spinal muscular atrophy (SMA) are currently underway. Biomarkers that document treatment-induced effects are needed because disease progression in childhood forms of SMA is slow and clinical outcome measures may lack sensitivity to detect meaningful changes in motor function in the period of 1-2 years of follow-up during randomized clinical trials. OBJECTIVE: To determine and compare SMN protein and mRNA levels in two cell types (i...
2016: PloS One
https://www.readbyqxmd.com/read/27891608/compensatory-axon-sprouting-for-very-slow-axonal-die-back-in-a-transgenic-model-of-spinal-muscular-atrophy-type-iii
#4
Esther Udina, Charles Putman, Luke Harris, N Tyreman, Victoria Cook, Tessa Gordon
Spinal muscular atrophy (SMA) is a common autosomal recessive disorder in humans and is the leading genetic cause of infantile death. Patients lack the SMN1 gene with the severity of the disease depending on the number of copies of the highly homologous SMN2 gene. Although motoneuron death in the Smn+/- transgenic mouse model of mildest form of SMA, SMA type III, has been reported, we have used retrograde tracing of sciatic and femoral motoneurons in the hindlimb with recording of muscle and motor unit isometric forces to count the number of motoneurons with intact neuromuscular connections...
November 28, 2016: Journal of Physiology
https://www.readbyqxmd.com/read/27882347/ml372-blocks-smn-ubiquitination-and-improves-spinal-muscular-atrophy-pathology-in-mice
#5
Mahlet B Abera, Jingbo Xiao, Jonathan Nofziger, Steve Titus, Noel Southall, Wei Zheng, Kasey E Moritz, Marc Ferrer, Jonathan J Cherry, Elliot J Androphy, Amy Wang, Xin Xu, Christopher Austin, Kenneth H Fischbeck, Juan J Marugan, Barrington G Burnett
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease and one of the leading inherited causes of infant mortality. SMA results from insufficient levels of the survival motor neuron (SMN) protein, and studies in animal models of the disease have shown that increasing SMN protein levels ameliorates the disease phenotype. Our group previously identified and optimized a new series of small molecules, with good potency and toxicity profiles and reasonable pharmacokinetics, that were able to increase SMN protein levels in SMA patient-derived cells...
November 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27843464/molecular-genetic-analysis-of-survival-motor-neuron-gene-in-460-turkish-cases-with-suspicious-spinal-muscular-atrophy-disease
#6
Afrooz Rashnonejad, Huseyin Onay, Tahir Atik, Ozlem Atan Sahin, Sarenur Gokben, Hasan Tekgul, Ferda Ozkinay
OBJECTIVE: To describe 12 yr experience of molecular genetic diagnosis of Spinal Muscular Atrophy (SMA) in 460 cases of Turkish patients. MATERIALS & METHODS: A retrospective analysis was performed on data from 460 cases, referred to Medical Genetics Laboratory, Ege University's Hospital, Izmir, Turkey, prediagnosed as SMA or with family history of SMA between 2003 and 2014. The PCR-restriction fragment length polymorphism (RFLP) and the Multiplex ligation-dependent probe amplification (MLPA) analysis were performed to detect the survival motor neuron (SMN)1 deletions and to estimate SMN1 and SMN2 gene copy numbers...
2016: Iranian Journal of Child Neurology
https://www.readbyqxmd.com/read/27754957/evaluation-and-comparison-of-three-assays-for-molecular-detection-of-spinal-muscular-atrophy
#7
Liang Li, Wan-Jun Zhou, Ping Fang, Ze-Yan Zhong, Jian-Sheng Xie, Ti-Zhen Yan, Jian Zeng, Xu-Hui Tan, Xiang-Min Xu
BACKGROUND: Spinal muscular atrophy (SMA) is mainly caused by deletions in SMA-related genes. The objective of this study was to develop gene-dosage assays for diagnosing SMA. METHODS: A multiplex, quantitative PCR assay and a CNVplex assay were developed for determining the copy number of SMN1, SMN2, and NAIP. Reproducibility and specificity of the two assays were compared to a multiple ligation-dependent probe amplification (MLPA) assay. To evaluate reproducibility, 30 samples were analyzed three times using the three assays...
October 18, 2016: Clinical Chemistry and Laboratory Medicine: CCLM
https://www.readbyqxmd.com/read/27726134/survival-of-motor-neurone-protein-is-required-for-normal-postnatal-development-of-the-spleen
#8
Alison K Thomson, Eilidh Somers, Rachael A Powis, Hannah K Shorrock, Kelley Murphy, Kathryn J Swoboda, Thomas H Gillingwater, Simon H Parson
Spinal muscular atrophy (SMA), traditionally described as a predominantly childhood form of motor neurone disease, is the leading genetic cause of infant mortality. Although motor neurones are undoubtedly the primary affected cell type, the severe infantile form of SMA (Type I SMA) is now widely recognised to represent a multisystem disorder where a variety of organs and systems in the body are also affected. Here, we report that the spleen is disproportionately small in the 'Taiwanese' murine model of severe SMA (Smn(-/-) ;SMN2(tg/0) ), correlated to low levels of cell proliferation and increased cell death...
October 11, 2016: Journal of Anatomy
https://www.readbyqxmd.com/read/27621445/systemic-peptide-mediated-oligonucleotide-therapy-improves-long-term-survival-in-spinal-muscular-atrophy
#9
Suzan M Hammond, Gareth Hazell, Fazel Shabanpoor, Amer F Saleh, Melissa Bowerman, James N Sleigh, Katharina E Meijboom, Haiyan Zhou, Francesco Muntoni, Kevin Talbot, Michael J Gait, Matthew J A Wood
The development of antisense oligonucleotide therapy is an important advance in the identification of corrective therapy for neuromuscular diseases, such as spinal muscular atrophy (SMA). Because of difficulties of delivering single-stranded oligonucleotides to the CNS, current approaches have been restricted to using invasive intrathecal single-stranded oligonucleotide delivery. Here, we report an advanced peptide-oligonucleotide, Pip6a-morpholino phosphorodiamidate oligomer (PMO), which demonstrates potent efficacy in both the CNS and peripheral tissues in severe SMA mice following systemic administration...
September 27, 2016: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/27528753/stars-in-the-cns
#10
REVIEW
Ingrid Ehrmann, Philippe Fort, David J Elliott
STAR (signal transduction and activation of RNA) proteins regulate splicing of target genes that have roles in neural connectivity, survival and myelination in the vertebrate nervous system. These regulated splicing targets include mRNAs such as the Neurexins (Nrxn), SMN2 (survival of motor neuron) and MAG (myelin-associated glycoprotein). Recent work has made it possible to identify and validate STAR protein splicing targets in vivo by using genetically modified mouse models. In this review, we will discuss the importance of STAR protein splicing targets in the CNS (central nervous system)...
August 15, 2016: Biochemical Society Transactions
https://www.readbyqxmd.com/read/27510309/genotype-phenotype-correlation-of-smn-locus-genes-in-spinal-muscular-atrophy-children-from-argentina
#11
Sofía Medrano, Soledad Monges, Luis Pablo Gravina, Laura Alías, Julieta Mozzoni, Hilda Verónica Aráoz, Sara Bernal, Angélica Moresco, Lilien Chertkoff, Eduardo Tizzano
BACKGROUND/PURPOSE: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder, considered one of the leading causes of infant mortality. It is caused by mutations in the SMN1 gene. A highly homologous copy of this gene named SMN2 and other neighbouring genes, SERF1A and NAIP, are considered phenotypic modifiers of the disease. In recent years, notable advances have been made in SMA research regarding evaluation, prognosis, and therapeutic options. Thus, genotype-phenotype studies in SMA are important to stratify patients for motor function tests and for envisaged clinical trials...
December 0: European Journal of Paediatric Neurology: EJPN
https://www.readbyqxmd.com/read/27499521/the-power-of-human-protective-modifiers-pls3-and-coro1c-unravel-impaired-endocytosis-in-spinal-muscular-atrophy-and-rescue-sma-phenotype
#12
Seyyedmohsen Hosseinibarkooie, Miriam Peters, Laura Torres-Benito, Raphael H Rastetter, Kristina Hupperich, Andrea Hoffmann, Natalia Mendoza-Ferreira, Anna Kaczmarek, Eva Janzen, Janine Milbradt, Tobias Lamkemeyer, Frank Rigo, C Frank Bennett, Christoph Guschlbauer, Ansgar Büschges, Matthias Hammerschmidt, Markus Riessland, Min Jeong Kye, Christoph S Clemen, Brunhilde Wirth
Homozygous loss of SMN1 causes spinal muscular atrophy (SMA), the most common and devastating childhood genetic motor-neuron disease. The copy gene SMN2 produces only ∼10% functional SMN protein, insufficient to counteract development of SMA. In contrast, the human genetic modifier plastin 3 (PLS3), an actin-binding and -bundling protein, fully protects against SMA in SMN1-deleted individuals carrying 3-4 SMN2 copies. Here, we demonstrate that the combinatorial effect of suboptimal SMN antisense oligonucleotide treatment and PLS3 overexpression-a situation resembling the human condition in asymptomatic SMN1-deleted individuals-rescues survival (from 14 to >250 days) and motoric abilities in a severe SMA mouse model...
September 1, 2016: American Journal of Human Genetics
https://www.readbyqxmd.com/read/27490705/small-molecules-in-development-for-the-treatment-of-spinal-muscular-atrophy
#13
Alyssa N Calder, Elliot J Androphy, Kevin J Hodgetts
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease resulting from pathologically low levels of survival motor neuron (SMN) protein. The majority of mRNA from the SMN2 allele undergoes alternative splicing and excludes critical codons, causing an SMN protein deficiency. While there is currently no FDA-approved treatment for SMA, early therapeutic efforts have focused on testing repurposed drugs such as phenylbutyrate (2), valproic acid (3), riluzole (6), hydroxyurea (7), and albuterol (9), none of which has demonstrated clinical effectiveness...
August 16, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27479447/synthetic-nucleic-acids-and-treatment-of-neurological-diseases
#14
David R Corey
Importance: The ability to control gene expression with antisense oligonucleotides (ASOs) could provide a new treatment strategy for disease. Objective: To review the use of ASOs for the treatment of neurological disorders. Evidence Review: Articles were identified through a search of PubMed references from 2000 to 2016 for articles describing the use of ASOs to treat disease, with specific attention to neurological disease. We concentrated our review on articles pertaining to activation of frataxin expression (Friedreich's ataxia) and production of active survival motor neuron 2 (SMN2, spinal muscular atrophy)...
October 1, 2016: JAMA Neurology
https://www.readbyqxmd.com/read/27456062/somatic-therapy-of-a-mouse-sma-model-with-a-u7-snrna-gene-correcting-smn2-splicing
#15
Philipp Odermatt, Judith Trüb, Lavinia Furrer, Roger Fricker, Andreas Marti, Daniel Schümperli
Spinal Muscular Atrophy (SMA) is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe SMA mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) AAV9 vector particles were optimized...
July 26, 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27401142/optimization-of-morpholino-antisense-oligonucleotides-targeting-the-intronic-repressor-element1-in-spinal-muscular-atrophy
#16
Erkan Y Osman, Charles W Washington, Kevin A Kaifer, Chiara Mazzasette, Teresa N Patitucci, Kyra M Florea, Madeline E Simon, Chien-Ping Ko, Allison D Ebert, Christian L Lorson
Loss of Survival Motor Neuron-1 (SMN1) causes Spinal Muscular Atrophy, a devastating neurodegenerative disease. SMN2 is a nearly identical copy gene; however SMN2 cannot prevent disease development in the absence of SMN1 since the majority of SMN2-derived transcripts are alternatively spliced, encoding a truncated, unstable protein lacking exon 7. Nevertheless, SMN2 retains the ability to produce low levels of functional protein. Previously we have described a splice-switching Morpholino antisense oligonucleotide (ASO) sequence that targets a potent intronic repressor, Element1 (E1), located upstream of SMN2 exon 7...
September 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/27353697/imaging-flow-cytometry-analysis-to-identify-differences-of-survival-motor-neuron-protein-expression-in-patients-with-spinal-muscular-atrophy
#17
Reiko Arakawa, Masayuki Arakawa, Kaori Kaneko, Noriko Otsuki, Ryoko Aoki, Kayoko Saito
BACKGROUND: Spinal muscular atrophy is a neurodegenerative disorder caused by the deficient expression of survival motor neuron protein in motor neurons. A major goal of disease-modifying therapy is to increase survival motor neuron expression. Changes in survival motor neuron protein expression can be monitored via peripheral blood cells in patients; therefore we tested the sensitivity and utility of imaging flow cytometry for this purpose. METHODS: After the immortalization of peripheral blood lymphocytes from a human healthy control subject and two patients with spinal muscular atrophy type 1 with two and three copies of SMN2 gene, respectively, we used imaging flow cytometry analysis to identify significant differences in survival motor neuron expression...
August 2016: Pediatric Neurology
https://www.readbyqxmd.com/read/27349908/differential-induction-of-muscle-atrophy-pathways-in-two-mouse-models-of-spinal-muscular-atrophy
#18
Marc-Olivier Deguise, Justin G Boyer, Emily R McFall, Armin Yazdani, Yves De Repentigny, Rashmi Kothary
Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn(2B/-) mice but not in the more severe Smn(-/-); SMN2 mice...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27299569/discovery-and-optimization-of-small-molecule-splicing-modifiers-of-survival-motor-neuron-2-as-a-treatment-for-spinal-muscular-atrophy
#19
Matthew G Woll, Hongyan Qi, Anthony Turpoff, Nanjing Zhang, Xiaoyan Zhang, Guangming Chen, Chunshi Li, Song Huang, Tianle Yang, Young-Choon Moon, Chang-Sun Lee, Soongyu Choi, Neil G Almstead, Nikolai A Naryshkin, Amal Dakka, Jana Narasimhan, Vijayalakshmi Gabbeta, Ellen Welch, Xin Zhao, Nicole Risher, Josephine Sheedy, Marla Weetall, Gary M Karp
The underlying cause of spinal muscular atrophy (SMA) is a deficiency of the survival motor neuron (SMN) protein. Starting from hits identified in a high-throughput screening campaign and through structure-activity relationship investigations, we have developed small molecules that potently shift the alternative splicing of the SMN2 exon 7, resulting in increased production of the full-length SMN mRNA and protein. Three novel chemical series, represented by compounds 9, 14, and 20, have been optimized to increase the level of SMN protein by >50% in SMA patient-derived fibroblasts at concentrations of <160 nM...
July 14, 2016: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/27299419/specific-correction-of-alternative-survival-motor-neuron-2-splicing-by-small-molecules-discovery-of-a-potential-novel-medicine-to-treat-spinal-muscular-atrophy
#20
Hasane Ratni, Gary M Karp, Marla Weetall, Nikolai A Naryshkin, Sergey V Paushkin, Karen S Chen, Kathleen D McCarthy, Hongyan Qi, Anthony Turpoff, Matthew G Woll, Xiaoyan Zhang, Nanjing Zhang, Tianle Yang, Amal Dakka, Priya Vazirani, Xin Zhao, Emmanuel Pinard, Luke Green, Pascale David-Pierson, Dietrich Tuerck, Agnes Poirier, Wolfgang Muster, Stephan Kirchner, Lutz Mueller, Irene Gerlach, Friedrich Metzger
Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein. SMN2, a paralogous gene to SMN1, undergoes alternative splicing and exclusion of exon 7, producing an unstable, truncated SMNΔ7 protein. Herein, we report the identification of a pyridopyrimidinone series of small molecules that modify the alternative splicing of SMN2, increasing the production of full-length SMN2 mRNA...
July 14, 2016: Journal of Medicinal Chemistry
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