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https://www.readbyqxmd.com/read/29149772/natural-history-of-infantile-onset-spinal-muscular-atrophy
#1
Stephen J Kolb, Christopher S Coffey, Jon W Yankey, Kristin Krosschell, W David Arnold, Seward B Rutkove, Kathryn J Swoboda, Sandra P Reyna, Ai Sakonju, Basil T Darras, Richard Shell, Nancy Kuntz, Diana Castro, Julie Parsons, Anne M Connolly, Claudia A Chiriboga, Craig McDonald, W Bryan Burnette, Klaus Werner, Mathula Thangarajh, Perry B Shieh, Erika Finanger, Merit E Cudkowicz, Michelle M McGovern, D Elizabeth McNeil, Richard Finkel, Susan T Iannaccone, Edward Kaye, Allison Kingsley, Samantha R Renusch, Vicki L McGovern, Xueqian Wang, Phillip G Zaworski, Thomas W Prior, Arthur H M Burghes, Amy Bartlett, John T Kissel
OBJECTIVE: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. METHODS: A longitudinal, multi-center, prospective natural history study enrolled 26 SMA infants, and 27 control infants less than six months of age...
November 17, 2017: Annals of Neurology
https://www.readbyqxmd.com/read/29133793/binding-to-smn2-pre-mrna-protein-complex-elicits-specificity-for-small-molecule-splicing-modifiers
#2
Manaswini Sivaramakrishnan, Kathleen D McCarthy, Sébastien Campagne, Sylwia Huber, Sonja Meier, Angélique Augustin, Tobias Heckel, Hélène Meistermann, Melanie N Hug, Pascale Birrer, Ahmed Moursy, Sarah Khawaja, Roland Schmucki, Nikos Berntenis, Nicolas Giroud, Sabrina Golling, Manuel Tzouros, Balazs Banfai, Gonzalo Duran-Pacheco, Jens Lamerz, Ying Hsiu Liu, Thomas Luebbers, Hasane Ratni, Martin Ebeling, Antoine Cléry, Sergey Paushkin, Adrian R Krainer, Frédéric H-T Allain, Friedrich Metzger
Small molecule splicing modifiers have been previously described that target the general splicing machinery and thus have low specificity for individual genes. Several potent molecules correcting the splicing deficit of the SMN2 (survival of motor neuron 2) gene have been identified and these molecules are moving towards a potential therapy for spinal muscular atrophy (SMA). Here by using a combination of RNA splicing, transcription, and protein chemistry techniques, we show that these molecules directly bind to two distinct sites of the SMN2 pre-mRNA, thereby stabilizing a yet unidentified ribonucleoprotein (RNP) complex that is critical to the specificity of these small molecules for SMN2 over other genes...
November 14, 2017: Nature Communications
https://www.readbyqxmd.com/read/29103974/optimization-of-a-series-of-heterocycles-as-survival-motor-neuron-gene-transcription-enhancers
#3
Sungwoon Choi, Alyssa N Calder, Eliza H Miller, Kierstyn P Anderson, Dawid K Fiejtek, Anne Rietz, Hongxia Li, Jonathan J Cherry, Kevin M Quist, Xuechao Xing, Marcie A Glicksman, Gregory D Cuny, Christian L Lorson, Elliot A Androphy, Kevin J Hodgetts
Spinal muscular atrophy (SMA) is a neurodegenerative disorder that results from mutations in the SMN1 gene, leading to survival motor neuron (SMN) protein deficiency. One therapeutic strategy for SMA is to identify compounds that enhance the expression of the SMN2 gene, which normally only is a minor contributor to functional SMN protein production, but which is unaffected in SMA. A recent high-throughput screening campaign identified a 3,4-dihydro-4-phenyl-2(1H)-quinolinone derivative (2) that increases the expression of SMN2 by 2-fold with an EC50 = 8...
October 26, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/29091570/nusinersen-versus-sham-control-in-infantile-onset-spinal-muscular-atrophy
#4
RANDOMIZED CONTROLLED TRIAL
Richard S Finkel, Eugenio Mercuri, Basil T Darras, Anne M Connolly, Nancy L Kuntz, Janbernd Kirschner, Claudia A Chiriboga, Kayoko Saito, Laurent Servais, Eduardo Tizzano, Haluk Topaloglu, Már Tulinius, Jacqueline Montes, Allan M Glanzman, Kathie Bishop, Z John Zhong, Sarah Gheuens, C Frank Bennett, Eugene Schneider, Wildon Farwell, Darryl C De Vivo
BACKGROUND: Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. METHODS: We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy...
November 2, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/29066780/survival-motor-neuron-protein-is-released-from-cells-in-exosomes-a-potential-biomarker-for-spinal-muscular-atrophy
#5
Leslie A Nash, Emily R McFall, Amanda M Perozzo, Maddison Turner, Kathy L Poulin, Yves De Repentigny, Joseph K Burns, Hugh J McMillan, Jodi Warman Chardon, Dylan Burger, Rashmi Kothary, Robin J Parks
Spinal muscular atrophy (SMA) is caused by homozygous mutation of the survival motor neuron 1 (SMN1) gene. Disease severity inversely correlates to the amount of SMN protein produced from the homologous SMN2 gene. We show that SMN protein is naturally released in exosomes from all cell types examined. Fibroblasts from patients or a mouse model of SMA released exosomes containing reduced levels of SMN protein relative to normal controls. Cells overexpressing SMN protein released exosomes with dramatically elevated levels of SMN protein...
October 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28983837/treatment-advances-in-spinal-muscular-atrophy
#6
REVIEW
Diana Bharucha-Goebel, Petra Kaufmann
PURPOSE OF REVIEW: Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development. RECENT FINDINGS: Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials...
October 6, 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28981879/activation-of-a-cryptic-5-splice-site-reverses-the-impact-of-pathogenic-splice-site-mutations-in-the-spinal-muscular-atrophy-gene
#7
Natalia N Singh, José Bruno Del Rio-Malewski, Diou Luo, Eric W Ottesen, Matthew D Howell, Ravindra N Singh
Spinal muscular atrophy (SMA) is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene coupled with predominant skipping of SMN2 exon 7. The only approved SMA treatment is an antisense oligonucleotide that targets the intronic splicing silencer N1 (ISS-N1), located downstream of the 5' splice site (5'ss) of exon 7. Here, we describe a novel approach to exon 7 splicing modulation through activation of a cryptic 5'ss (Cr1). We discovered the activation of Cr1 in transcripts derived from SMN1 that carries a pathogenic G-to-C mutation at the first position (G1C) of intron 7...
September 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977438/spinal-muscular-atrophy-antisense-oligonucleotide-therapy-opens-the-door-to-an-integrated-therapeutic-landscape
#8
Matthew J A Wood, Kevin Talbot, Melissa Bowerman
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMNΔ7 protein, but from which functional full length SMN protein is produced at very low levels (∼10%)...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28962115/application-of-urine-cells-in-drug-intervention-for-spinal-muscular-atrophy
#9
Qi-Jie Zhang, Xiang Lin, Jin-Jing Li, Ying-Qian Lu, Xin-Xin Guo, En-Lin Dong, Miao Zhao, Jin He, Ning Wang, Wan-Jin Chen
Spinal muscular atrophy (SMA) is a lethal childhood neurodegenerative disorder that is caused by the homozygous deletion of survival motor neuron 1 (SMN1). To date, no effective treatments are available. In the current study, urine cells taken from SMA patients were cultured and the application of patient-derived urine cells was determined in drug intervention. A total of 13 SMA patient-derived urine cell lines and 40 control cell lines were established. SMN was highly expressed in the nucleus and cytoplasm...
September 2017: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/28945765/in-vitro-and-in-vivo-effects-of-2-4-diaminoquinazoline-inhibitors-of-the-decapping-scavenger-enzyme-dcps-context-specific-modulation-of-smn-transcript-levels
#10
Jonathan J Cherry, Christine J DiDonato, Elliot J Androphy, Alessandro Calo, Kyle Potter, Sara K Custer, Sarah Du, Timothy L Foley, Ariamala Gopalsamy, Emily J Reedich, Susana M Gordo, William Gordon, Natalie Hosea, Lyn H Jones, Daniel K Krizay, Gregory LaRosa, Hongxia Li, Sachin Mathur, Carol A Menard, Paraj Patel, Rebeca Ramos-Zayas, Anne Rietz, Haojing Rong, Baohong Zhang, Michael A Tones
C5-substituted 2,4-diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS (DAQ-DcpSi) have been developed for the treatment of spinal muscular atrophy (SMA), which is caused by genetic deficiency in the Survival Motor Neuron (SMN) protein. These compounds are claimed to act as SMN2 transcriptional activators but data underlying that claim are equivocal. In addition it is unclear whether the claimed effects on SMN2 are a direct consequence of DcpS inhibitor or might be a consequence of lysosomotropism, which is known to be neuroprotective...
2017: PloS One
https://www.readbyqxmd.com/read/28899515/the-water-extract-of-liuwei-dihuang-possesses-multi-protective-properties-on-neurons-and-muscle-tissue-against-deficiency-of-survival-motor-neuron-protein
#11
Yu-Ting Tseng, Yuh-Jyh Jong, Wei-Fang Liang, Fang-Rong Chang, Yi-Ching Lo
BACKGROUND: Deficiency of survival motor neuron (SMN) protein, which is encoded by the SMN1 and SMN2 genes, induces widespread splicing defects mainly in spinal motor neurons, and leads to spinal muscular atrophy (SMA). Currently, there is no effective treatment for SMA. Liuwei dihuang (LWDH), a traditional Chinese herbal formula, possesses multiple therapeutic benefits against various diseases via modulation of the nervous, immune and endocrine systems. Previously, we demonstrated water extract of LWDH (LWDH-WE) protects dopaminergic neurons and improves motor activity in models of Parkinson's disease...
October 15, 2017: Phytomedicine: International Journal of Phytotherapy and Phytopharmacology
https://www.readbyqxmd.com/read/28799578/nusinersen-antisense-oligonucleotide-to-increase-smn-protein-production-in-spinal-muscular-atrophy
#12
REVIEW
D M Paton
Patients with spinal muscular atrophy (SMA) have an autosomal recessive disease that limits their ability to produce survival motor neuron (SMN) protein in the CNS resulting in progressive wasting of voluntary muscles. Detailed studies over several years have demonstrated that phosphorothioate and 2'-O-methoxyethyl- modified antisense oligonucleotides (ASOs) targeting the ISS-N1 site increase SMN2 exon 7 inclusion, thus increasing levels of SMN protein in a dose- and time-dependent manner in liver, kidney and skeletal muscle, and CNS tissues only when administered intrathecally...
June 2017: Drugs of Today
https://www.readbyqxmd.com/read/28797588/longitudinal-assessments-in-discordant-twins-with-sma
#13
Marika Pane, Leonardo Lapenta, Emanuela Abiusi, Roberto de Sanctis, Marco Luigetti, Concetta Palermo, Domiziana Ranalli, Stefania Fiori, Francesco Danilo Tiziano, Eugenio Mercuri
We report longitudinal clinical and neurophysiological assessments in twins affected by spinal muscular atrophy (SMA) with discordant phenotypes. The boy had the homozygous deletion of SMN1, a typical type 1 SMA course, and died at the age of eight months. His twin sister, asymptomatic at the time of the diagnosis in her brother, had the same genetic defect but she developed clinical and electrophysiological signs of type 2 SMA. The reduction of tendon reflexes was the first clinical sign at the age of 4 months, followed within few weeks, by a mild decrement in the amplitude of the compound motor action potentials...
July 8, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28775379/tia1-is-a-gender-specific-disease-modifier-of-a-mild-mouse-model-of-spinal-muscular-atrophy
#14
Matthew D Howell, Eric W Ottesen, Natalia N Singh, Rachel L Anderson, Joonbae Seo, Senthilkumar Sivanesan, Elizabeth M Whitley, Ravindra N Singh
Spinal muscular atrophy (SMA) is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. The nearly identical SMN2 cannot compensate for SMN1 loss due to exon 7 skipping. The allele C (C (+/+)) mouse recapitulates a mild SMA-like phenotype and offers an ideal system to monitor the role of disease-modifying factors over a long time. T-cell-restricted intracellular antigen 1 (TIA1) regulates SMN exon 7 splicing. TIA1 is reported to be downregulated in obese patients, although it is not known if the effect is gender-specific...
August 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28768735/therapeutic-strategies-for-spinal-muscular-atrophy-smn-and-beyond
#15
REVIEW
Melissa Bowerman, Catherina G Becker, Rafael J Yáñez-Muñoz, Ke Ning, Matthew J A Wood, Thomas H Gillingwater, Kevin Talbot
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1 A second duplicated gene, SMN2, produces very little but sufficient functional protein for survival. Therapeutic strategies to increase SMN are in clinical trials, and the first SMN2-directed antisense oligonucleotide (ASO) therapy has recently been licensed...
August 1, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28757001/spinal-muscular-atrophy-a-changing-phenotype-beyond-the-clinical-trials
#16
REVIEW
Eduardo F Tizzano, Richard S Finkel
Spinal muscular atrophy is a monogenic, progressive motor neuron disorder caused by deletion or mutation in the SMN1 gene. A broad range of phenotypic severity, from very weak infants (Type 1) to ambulant children (type 3), is modified mainly by the number of copies of the "backup" SMN2 gene. Since the discovery of the role of both genes, basic research into the pathobiology of SMA, with in vitro and animal model studies, has identified therapeutic targets. Development of clinical outcome measures, natural history studies and standard of care guidelines have contributed to the development of protocols for therapeutic drugs now under clinical investigation...
October 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28755059/nusinersen-the-first-option-beyond-supportive-care-for-spinal-muscular-atrophy
#17
REVIEW
Vikas Maharshi, Shazia Hasan
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by degeneration of spinal motor neurons and poses significant adverse outcome in affected population. Survival motor neuron 1 (SMN1) protein encoded by SMN1 gene located on 5q(13) is critical for survival and functioning of motor neurons. Almost identical gene SMN2, present on the same chromosome, produces a small truncated protein (SMN2) because of skipping of exon 7 from translation due to translation silent C6U substitution in exon 7 of SMN2 pre-mRNA transcript...
July 28, 2017: Clinical Drug Investigation
https://www.readbyqxmd.com/read/28728573/splicing-arrays-reveal-novel-rbm10-targets-including-smn2-pre-mrna
#18
Leslie C Sutherland, Philippe Thibault, Mathieu Durand, Elvy Lapointe, Jose M Knee, Ariane Beauvais, Irina Kalatskaya, Sarah C Hunt, Julie J Loiselle, Justin G Roy, Sarah J Tessier, Gustavo Ybazeta, Lincoln Stein, Rashmi Kothary, Roscoe Klinck, Benoit Chabot
BACKGROUND: RBM10 is an RNA binding protein involved in message stabilization and alternative splicing regulation. The objective of the research described herein was to identify novel targets of RBM10-regulated splicing. To accomplish this, we downregulated RBM10 in human cell lines, using small interfering RNAs, then monitored alternative splicing, using a reverse transcription-PCR screening platform. RESULTS: RBM10 knockdown (KD) provoked alterations in splicing events in 10-20% of the pre-mRNAs, most of which had not been previously identified as RBM10 targets...
July 20, 2017: BMC Molecular Biology
https://www.readbyqxmd.com/read/28711173/presymptomatic-diagnosis-of-spinal-muscular-atrophy-through-newborn-screening
#19
Yin-Hsiu Chien, Shu-Chuan Chiang, Wen-Chin Weng, Ni-Chung Lee, Ching-Jie Lin, Wu-Shiun Hsieh, Wang-Tso Lee, Yuh-Jyh Jong, Tsang-Ming Ko, Wuh-Liang Hwu
OBJECTIVE: To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS). STUDY DESIGN: We performed a screening trial to assess all newborns who underwent routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples...
July 12, 2017: Journal of Pediatrics
https://www.readbyqxmd.com/read/28684086/modifier-genes-moving-from-pathogenesis-to-therapy
#20
Edward R B McCabe
This commentary will focus on how we can use our knowledge about the complexity of human disease and its pathogenesis to identify novel approaches to therapy. We know that even for single gene Mendelian disorders, patients with identical mutations often have different presentations and outcomes. This lack of genotype-phenotype correlation led us and others to examine the roles of modifier genes in the context of biological networks. These investigations have utilized vertebrate and invertebrate model organisms...
September 2017: Molecular Genetics and Metabolism
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