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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
#1
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
#2
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
#3
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
#4
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
#5
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
#6
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...
May 17, 2017: Neuromuscular Disorders: NMD
https://www.readbyqxmd.com/read/28755059/nusinersen-the-first-option-beyond-supportive-care-for-spinal-muscular-atrophy
#7
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
#8
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
#9
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
#10
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...
May 30, 2017: Molecular Genetics and Metabolism
https://www.readbyqxmd.com/read/28666123/splicing-correcting-therapy-for-sma
#11
Lili Wan, Gideon Dreyfuss
Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C→T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28662219/the-effects-of-c5-substituted-2-4-diaminoquinazolines-on-selected-transcript-expression-in-spinal-muscular-atrophy-cells
#12
Cinsley Gentillon, Andrew J Connell, Ryan W Kirk, Matthew E R Butchbach
C5-substituted 2,4-diaminoquinazolines (2,4-DAQs) ameliorate disease severity in SMA mice. It is uncertain, however, that these compounds increase SMN protein levels in vivo even though they were identified as activators of the SMN2 promoter. These compounds also regulate the expression of other transcripts in neuroblastoma cells. In this study, we investigate the mechanism by which the 2,4-DAQs regulate the expression of SMN2 as well as other targets. D156844, D158872, D157161 and D157495 (RG3039) increased SMN2 promoter-driven reporter gene activity by at least 3-fold in NSC-34 cells...
2017: PloS One
https://www.readbyqxmd.com/read/28648462/cyclic-tetrapeptide-hdac-inhibitors-as-potential-therapeutics-for-spinal-muscular-atrophy-screening-with-ipsc-derived-neuronal-cells
#13
Jiun-I Lai, Luke J Leman, Sherman Ku, Chris J Vickers, Christian A Olsen, Ana Montero, M Reza Ghadiri, Joel M Gottesfeld
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder that is caused by inactivating mutations in the Survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression. Humans possess a paralog gene, SMN2, which contains a splicing defect in exon 7 leading to diminished expression of full-length, fully functional SMN protein. Increasing SMN2 expression has been a focus of therapeutic development for SMA. Multiple studies have reported the efficacy of histone deacetylase inhibitors (HDACi) in this regard...
August 1, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#14
REVIEW
K Talbot, E F Tizzano
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy...
June 23, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28639617/gene-therapy-for-spinomuscular-atrophy-a-biomedical-advance-a-missed-opportunity-for-more-equitable-drug-pricing
#15
T Friedmann
An experimental approach for gene therapy of spinomuscular atrophy has been reported to prevent development of the neuromuscular features of this lethal and previously untreatable disorder. The approach involves treatment of patients suffering from SMN1-associated infantile form of the disease with a splice-switching antisense oligonucleotide (ASO) that corrects aberrant splicing of the nearly identical SMN2 gene to allow the generation of functional SMN protein, thereby mitigating the development of the disease...
June 22, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28624227/efficient-smn-rescue-following-subcutaneous-tricyclo-dna-antisense-oligonucleotide-treatment
#16
Valérie Robin, Graziella Griffith, John-Paul L Carter, Christian J Leumann, Luis Garcia, Aurélie Goyenvalle
Spinal muscular atrophy (SMA) is a recessive disease caused by mutations in the SMN1 gene, which encodes the protein survival motor neuron (SMN), whose absence dramatically affects the survival of motor neurons. In humans, the severity of the disease is lessened by the presence of a gene copy, SMN2. SMN2 differs from SMN1 by a C-to-T transition in exon 7, which modifies pre-mRNA splicing and prevents successful SMN synthesis. Splice-switching approaches using antisense oligonucleotides (AONs) have already been shown to correct this SMN2 gene transition, providing a therapeutic avenue for SMA...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28623256/lna-dna-mixmer-based-antisense-oligonucleotides-correct-alternative-splicing-of-the%C3%A2-smn2-gene-and-restore-smn-protein-expression-in-type-1-sma-fibroblasts
#17
Aleksander Touznik, Rika Maruyama, Kana Hosoki, Yusuke Echigoya, Toshifumi Yokota
Spinal muscular atrophy (SMA) is an autosomal recessive disorder affecting motor neurons, and is currently the most frequent genetic cause of infant mortality. SMA is caused by a loss-of-function mutation in the survival motor neuron 1 (SMN1) gene. SMN2 is an SMN1 paralogue, but cannot compensate for the loss of SMN1 since exon 7 in SMN2 mRNA is excluded (spliced out) due to a single C-to-T nucleotide transition in the exon 7. One of the most promising strategies to treat SMA is antisense oligonucleotide (AON)-mediated therapy...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28601407/relationships-between-long-term-observations-of-motor-milestones-and-genotype-analysis-results-in-childhood-onset-japanese-spinal-muscular-atrophy-patients
#18
Kaori Kaneko, Reiko Arakawa, Mari Urano, Ryoko Aoki, Kayoko Saito
AIM: To clarify the long-term natural history of SMA in Japanese patients by investigating the peak motor milestones of cases 7months through 57years of age, in efforts to contribute to evaluating outcomes of new therapeutic interventions. METHODS: We sub-classified 112 SMA type I-III cases into type Ia, type Ib, type IIa, type IIb, type IIIa and type IIIb, according to peak motor milestone achieved, and analyzed the SMN1, SMN2 and NAIP genes in relation to clinical subtypes...
June 7, 2017: Brain & Development
https://www.readbyqxmd.com/read/28598854/analysis-of-azithromycin-monohydrate-as-a-single-or-a-combinatorial-therapy-in-a-mouse-model-of-severe-spinal-muscular-atrophy
#19
Erkan Y Osman, Charles W Washington, Madeline E Simon, Dalia Megiddo, Hagar Greif, Christian L Lorson
BACKGROUND: Spinal muscular atrophy (SMA) is a neurodegenerative autosomal recessive disorder characterized by the loss of α-motor neurons. A variety of molecular pathways are being investigated to elevate SMN protein expression in SMA models and in the clinic. One of these approaches involves stabilizing the SMNΔ7 protein by inducing translational read-through. Previous studies have demonstrated that functionality and stability are partially restored to the otherwise unstable SMNΔ7 by the addition of non-specific C-terminal peptide sequences, or by inducing a similar molecular event through the use of read-through inducing compounds such as aminoglycosides...
June 9, 2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28598128/-molecular-features-of-sma-related-genes-in-spinal-muscular-atrophy-patients-of-han-nationality-in-southwest-china
#20
Min-Jin Wang, Jun Wang, Meng-Ge Bai, Wen-Jing Zhou, Li-Juan Wu, Si-Shi Tang, Xiao-Jun Lu, Bin-Wu Ying
OBJECTIVES: To investigate the molecular features of spinal muscular atrophy (SMA) related genes in SMA patients of Han nationality of southwest of China. METHODS: We collected 62 unrelated patients of SMA and 50 unrelated healthy individuals in this study.The copy numbers of survival motor neuron gene (SMN) and uronal-apoptosis inhibitory protein gene (NAIP) were measured by using multiplex ligation-dependent probe amplification (MLPA). RESULTS: Of 62 patients,the copy number of SMA1-4 were 30...
November 2016: Sichuan da Xue Xue Bao. Yi Xue Ban, Journal of Sichuan University. Medical Science Edition
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