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https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#1
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
#2
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/28637335/astrocyte-produced-mir-146a-as-a-mediator-of-motor-neuron-loss-in-spinal-muscular-atrophy
#3
Samantha L Sison, Teresa N Patitucci, Emily R Seminary, Eric Villalon, Christian L Lorson, Allison D Ebert
Spinal muscular atrophy (SMA), the leading genetic cause of infant mortality, is caused by loss of the survival motor neuron-1 (SMN1) gene, which leads to motor neuron loss, muscle atrophy, respiratory distress, and death. Motor neurons exhibit the most profound loss, but the mechanisms underlying disease pathogenesis are not fully understood. Recent evidence suggests that motor neuron extrinsic influences, such as those arising from astrocytes, contribute to motor neuron malfunction and loss. Here we investigated both loss-of-function and toxic gain-of-function astrocyte mechanisms that could play a role in SMA pathology...
June 15, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28634652/a-multi-source-approach-to-determine-sma-incidence-and-research-ready-population
#4
Ingrid E C Verhaart, Agata Robertson, Rebecca Leary, Grace McMacken, Kirsten König, Janbernd Kirschner, Cynthia C Jones, Suzanne F Cook, Hanns Lochmüller
In spinal muscular atrophy (SMA), degeneration of motor neurons causes progressive muscular weakness, which is caused by homozygous deletion of the SMN1 gene. Available epidemiological data on SMA are scarce, often outdated, and limited to relatively small regions or populations. Combining data from different sources including genetic laboratories and patient registries may provide better insight of the disease epidemiology. To investigate the incidence of genetically confirmed SMA, and the number of patients who are able and approachable to participate in new clinical trials and observational research, we used both genetic laboratories, the TREAT-NMD Global SMA Patient Registry and the Care and Trial Sites Registry (CTSR)...
June 20, 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28634552/inherited-paediatric-motor-neuron-disorders-beyond-spinal-muscular-atrophy
#5
REVIEW
Hooi Ling Teoh, Kate Carey, Hugo Sampaio, David Mowat, Tony Roscioli, Michelle Farrar
Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28624227/efficient-smn-rescue-following-subcutaneous-tricyclo-dna-antisense-oligonucleotide-treatment
#6
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
#7
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
#8
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/28598128/-molecular-features-of-sma-related-genes-in-spinal-muscular-atrophy-patients-of-han-nationality-in-southwest-china
#9
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
https://www.readbyqxmd.com/read/28577599/molecular-inversion-probes-equipped-with-discontinuous-rolling-cycle-amplification-for-targeting-nucleotide-variants-determining-smn1-and-smn2-genes-in-diagnosis-of-spinal-muscular-atrophy
#10
Hwang-Shang Kou, Chun-Chi Wang
The novel techniques of molecular inversion probes (MIPs) combined with discontinuous rolling cycle amplification (DRCA) was developed for determination of the multi-nucleotide variants at single base. The different-length MIPs, a padlock-probe based technology, are designed to simultaneously recognize the identical nucleotide variants. After ligation and DRCA, the different-length genetic products representing the certain genotypes could be simply determined by the short-end capillary electrophoresis (CE) method...
July 18, 2017: Analytica Chimica Acta
https://www.readbyqxmd.com/read/28570645/how-do-sma-linked-mutations-of-smn1-lead-to-structural-functional-deficiency-of-the-sma-protein
#11
Wei Li
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease with dysfunctional α-motor neurons in the anterior horn of the spinal cord. SMA is caused by loss (∼95% of SMA cases) or mutation (∼5% of SMA cases) of the survival motor neuron 1 gene SMN1. As the product of SMN1, SMN is a component of the SMN complex, and is also involved in the biosynthesis of the small nuclear ribonucleoproteins (snRNPs), which play critical roles in pre-mRNA splicing in the pathogenesis of SMA. To investigate how SMA-linked mutations of SMN1 lead to structural/functional deficiency of SMN, a set of computational analysis of SMN-related structures were conducted and are described in this article...
2017: PloS One
https://www.readbyqxmd.com/read/28561813/therapeutic-approaches-for-spinal-muscular-atrophy-sma
#12
REVIEW
M Scoto, R S Finkel, E Mercuri, F Muntoni
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterized by progressive muscle wasting and loss of muscle function due to severe motor neuron dysfunction, secondary to mutations in the survival motor neuron 1 (SMN1) gene. A second neighboring centromeric gene, SMN2, is intact in all patients but contains a C-to-T variation in exon 7 that affects a splice enhancer and determines exclusion of exon 7 in the majority of its transcript, leading to an unstable protein that cannot substitute for mutant SMN1...
May 31, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28556834/developmental-regulation-of-smn-expression-pathophysiological-implications-and-perspectives-for-therapy-development-in-spinal-muscular-atrophy
#13
REVIEW
S Jablonka, M Sendtner
Spinal muscular atrophy (SMA), the predominant form of motoneuron diease in children and young adults is caused by loss of function of the SMN protein. On the basis of a disrupted splice acceptor site in exon 7, transcripts from a second SMN gene in humans called SMN2 cannot give rise to SMN protein at sufficient levels for maintaining function of motoneurons and motor circuits. First clinical trials with Spinraza/Nusinersen, a drug that counteracts disrupted splicing of SMN2 transcripts, have shown that elevating SMN levels can successfully interfere with motoneuron dysfunction...
May 30, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28524214/-possible-treatments-for-infantile-spinal-atrophy
#14
S I Pascual-Pascual, M Garcia-Romero
The new treatments of spinal muscular atrophy (SMA) due by SMN1 gene deletions are reviewed. There are several ways to increase the protein SMN, its activity and persistence in the tissues. Neuroprotective drugs as olesoxime or riluzole, and drugs acting by epigenetic mechanisms, as histone deacetylase inhibitors, have shown positive effects in preclinical studies but no clear efficacy in clinical trials. They might give in the future added benefits when used associated to other genetic modifying drugs. The best improvements in murine models of SMA and in clinical trials have been reached with antisense oligonucleotides, drugs that modify the splicing of SMN2, and they are expected to get better in the near future...
May 17, 2017: Revista de Neurologia
https://www.readbyqxmd.com/read/28522225/genetic-screening-of-spinal-muscular-atrophy-using-a-real-time-modified-cop-pcr-technique-with-dried-blood-spot-dna
#15
Mawaddah Ar Rochmah, Nur Imma Fatimah Harahap, Emma Tabe Eko Niba, Kenta Nakanishi, Hiroyuki Awano, Ichiro Morioka, Kazumoto Iijima, Toshio Saito, Kayoko Saito, Poh San Lai, Yasuhiro Takeshima, Atsuko Takeuchi, Yoshihiro Bouike, Maya Okamoto, Hisahide Nishio, Masakazu Shinohara
BACKGROUND: Spinal muscular atrophy (SMA) is a common neuromuscular disorder caused by mutations in SMN1. More than 95% of SMA patients carry homozygous SMN1 deletion. SMA is the leading genetic cause of infant death, and has been considered an incurable disease. However, a recent clinical trial with an antisense oligonucleotide drug has shown encouraging clinical efficacy. Thus, early and accurate detection of SMN1 deletion may improve prognosis of many infantile SMA patients. METHODS: A total of 88 DNA samples (37 SMA patients, 12 carriers and 39 controls) from dried blood spots (DBS) on filter paper were analyzed...
May 15, 2017: Brain & Development
https://www.readbyqxmd.com/read/28489755/kennedy-disease-with-difficulty-in-differential-diagnosis-a-case-report
#16
Yating Chen, Peng Luo, Zhongli Li, Hengping Hu, Duobin Wu, Tingting Xu, Xingzuo Wang, Haiting Xie
RATIONALE: Kennedy disease (KD) is also known as spinal bulbar muscular dystrophy. As KD has similar symptoms with most neuromuscular diseases, so it is difficult to make a rapid diagnosis clinically. PATIENT CONCERNS: We report a case of a 43-year-old male with progressive limb proximal weakness without family history. Physical examination showed gynecomastia, erectile dysfunction, bilateral tendon reflex and quadriceps weakness, and tongue muscle atrophy. DIAGNOSES: Laboratory examination found increased creatine kinase, impaired glucose tolerance, and abnormal lactic acid values...
May 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28485722/how-the-discovery-of-iss-n1-led-to-the-first-medical-therapy-for-spinal-muscular-atrophy
#17
REVIEW
N N Singh, M D Howell, E J Androphy, R N Singh
Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7 during pre-mRNA splicing. With the recent FDA approval of nusinersen (Spinraza™), the potential for correction of SMN2 exon 7 splicing as a SMA therapy has been affirmed. Nusinersen is an antisense oligonucleotide that targets intronic splicing silencer N1 (ISS-N1) discovered in 2004 at the University of Massachusetts Medical School...
May 9, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28460014/a-44g-transition-in-smn2-intron-6-protects-patients-with-spinal-muscular-atrophy
#18
Xingxing Wu, Shu-Huei Wang, Junjie Sun, Adrian R Krainer, Yimin Hua, Thomas W Prior
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by reduced expression of survival of motor neuron (SMN), a protein expressed in humans by two paralogous genes, SMN1 and SMN2. These genes are nearly identical, except for 10 single-nucleotide differences and a 5-nucleotide insertion in SMN2. SMA is subdivided into four main types, with type I being the most severe. SMN2 copy number is a key positive modifier of the disease, but it is not always inversely correlated with clinical severity. We previously reported the c...
April 28, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28456383/adult-onset-spinal-muscular-atrophy-an-update
#19
REVIEW
R Juntas Morales, N Pageot, G Taieb, W Camu
Spinal muscular atrophy (SMA) refers to a group of disorders affecting lower motor neurons. The age of onset of these disorders is variable, ranging from the neonatal period to adulthood. Over the last few years, there has been enormous progress in the description of new genes and phenotypes that throw new light on the molecular pathways involved in motor neuron degeneration. Advances in our understanding of the pathophysiology of the most frequent forms, SMA linked to SMN1 gene mutations and Kennedy disease, has led to the development of therapeutic strategies currently being tested in clinical trials...
April 26, 2017: Revue Neurologique
https://www.readbyqxmd.com/read/28450545/decreased-motor-neuron-support-by-sma-astrocytes-due-to-diminished-mcp1-secretion
#20
Jasmin E Martin, TrangKimberly T Nguyen, Christopher Grunseich, Jonathan H Nofziger, Philip R Lee, Douglas Fields, Kenneth H Fischbeck, Emily Foran
Spinal muscular atrophy (SMA) is an autosomal-recessive disorder characterized by severe, often fatal muscle weakness due to loss of motor neurons. SMA patients have deletions and other mutations of the survival of motor neuron 1 (SMN1) gene, resulting in decreased SMN protein. Astrocytes are the primary support cells of the CNS and are responsible for glutamate clearance, metabolic support, response to injury, and regulation of signal transmission. Astrocytes have been implicated in SMA as in in other neurodegenerative disorders...
May 24, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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