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https://www.readbyqxmd.com/read/29916015/mechanism-of-splicing-regulation-of-spinal-muscular-atrophy-genes
#1
Ravindra N Singh, Natalia N Singh
Spinal muscular atrophy (SMA) is one of the major genetic disorders associated with infant mortality. More than 90% cases of SMA result from deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, does not compensate for the loss of SMN1 due to predominant skipping of exon 7. However, correction of SMN2 exon 7 splicing has proven to confer therapeutic benefits in SMA patients. The only approved drug for SMA is an antisense oligonucleotide (Spinraza™/Nusinersen), which corrects SMN2 exon 7 splicing by blocking intronic splicing silencer N1 (ISS-N1) located immediately downstream of exon 7...
2018: Advances in Neurobiology
https://www.readbyqxmd.com/read/29889467/-nusinersen-in-the-treatment-of-spinal-muscular-atrophy
#2
REVIEW
Gabriella Sinkó, Zsuzsanna Kiss, Bernadette Kalman
Until recently, the diagnosis of spinal muscular atrophy (SMA) has been associated with severe life-long motor disability in adults and with early death in infants. The new experimental therapeutic approaches of the last few years have become more and more promising, while nusinersen was approved for the treatment of SMA in December 2016 in the USA, and in May 2017 in Hungary. Our paper presents mechanisms and clinical benefits of this new medication, and highlights some of the other therapeutic strategies still in experimental stages...
March 30, 2018: Ideggyógyászati Szemle
https://www.readbyqxmd.com/read/29865090/evaluator-training-and-reliability-for-sma-global-nusinersen-trials1
#3
Allan M Glanzman, Elena S Mazzone, Sally Dunaway Young, Richard Gee, Kristy Rose, Anna Mayhew, Leslie Nelson, Chris Yun, Katie Alexander, Basil T Darras, Zarazuela Zolkipli-Cunningham, Gihan Tennekoon, John W Day, Richard S Finkel, Eugenio Mercuri, Darryl C De Vivo, Ron Baldwin, Kathie M Bishop, Jacqueline Montes
BACKGROUND: Training methodology was established to optimize reliability of outcome measures in the nusinersen clinical trials. The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND), Hammersmith Functional Motor Scale Expanded (HFMSE), and Revised Upper Limb (RULM) were primary or secondary outcomes. METHODS: Video review, quarterly conference calls, and item scoring checks supported evaluator competence. Baseline and screening along with video review established intra and inter-rater reliability...
2018: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/29806836/evaluation-of-exon-inclusion-induced-by-splice-switching-antisense-oligonucleotides-in-sma-patient-fibroblasts
#4
Rika Maruyama, Aleksander Touznik, Toshifumi Yokota
Spinal muscular atrophy (SMA), a lethal neurological disease caused by the loss of SMN1, presents a unique case in the field of antisense oligonucleotide (AON)-mediated therapy. While SMN1 mutations are responsible for the disease, AONs targeting intronic splice silencer (ISS) sites in SMN2, including FDA-approved nusinersen, have been shown to restore SMN expression and ameliorate the symptoms. Currently, many studies involving AON therapy for SMA focus on investigating novel AON chemistries targeting SMN2 that may be more effective and less toxic than nusinersen...
May 11, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29801053/cost-effectiveness-of-nusinersen-for-spinal-muscular-atrophy
#5
Randal Charles Richardson
No abstract text is available yet for this article.
May 7, 2018: JAMA Pediatrics
https://www.readbyqxmd.com/read/29800980/cost-effectiveness-of-nusinersen-for-spinal-muscular-atrophy-reply
#6
Vinay Prasad
No abstract text is available yet for this article.
May 7, 2018: JAMA Pediatrics
https://www.readbyqxmd.com/read/29710299/concerns-about-the-approval-of-nusinersen-sodium-by-the-us-food-and-drug-administration
#7
Martha S Gerrity, Vinay Prasad, Adam J Obley
No abstract text is available yet for this article.
June 1, 2018: JAMA Internal Medicine
https://www.readbyqxmd.com/read/29689734/evaluation-of-children-with-sma-type-1-under-treatment-with-nusinersen-within-the-expanded-access-program-in-germany
#8
Astrid Pechmann, Thorsten Langer, David Schorling, Sabine Stein, Sibylle Vogt, Ulrike Schara, Heike Kölbel, Oliver Schwartz, Andreas Hahn, Kerstin Giese, Jessika Johannsen, Jonas Denecke, Claudia Weiß, Manuela Theophil, Janbernd Kirschner
BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle weakness and muscle atrophy. Nusinersen acts as a splicing modifier and has recently been approved for intrathecal treatment of SMA. OBJECTIVE: Prior to approval, nusinersen was provided to patients with SMA type 1 in Germany within an Expanded Access Program (EAP). In contrast to previous clinical trials, children of different age groups and different stages of the disease were treated with nusinersen...
2018: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/29672717/antisense-oligonucleotides-correct-the-familial-dysautonomia-splicing-defect-in-ikbkap-transgenic-mice
#9
Rahul Sinha, Young Jin Kim, Tomoki Nomakuchi, Kentaro Sahashi, Yimin Hua, Frank Rigo, C Frank Bennett, Adrian R Krainer
Familial dysautonomia (FD) is a rare inherited neurodegenerative disorder caused by a point mutation in the IKBKAP gene that results in defective splicing of its pre-mRNA. The mutation weakens the 5' splice site of exon 20, causing this exon to be skipped, thereby introducing a premature termination codon. Though detailed FD pathogenesis mechanisms are not yet clear, correcting the splicing defect in the relevant tissue(s), thus restoring normal expression levels of the full-length IKAP protein, could be therapeutic...
June 1, 2018: Nucleic Acids Research
https://www.readbyqxmd.com/read/29620999/dose-dependent-lowering-of-mutant-huntingtin-using-antisense-oligonucleotides-in-huntington-disease-patients
#10
Willeke M C van Roon-Mom, Raymund A C Roos, Susanne T de Bot
On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data...
April 2018: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/29568328/nusinersen-for-spinal-muscular-atrophy
#11
EDITORIAL
Claudia D Wurster, Albert C Ludolph
No abstract text is available yet for this article.
2018: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/29567652/transforaminal-lumbar-puncture-an-alternative-technique-in-patients-with-challenging-access
#12
D R Nascene, C Ozutemiz, H Estby, A M McKinney, J B Rykken
Interlaminar lumbar puncture and cervical puncture may not be ideal in all circumstances. Recently, we have used a transforaminal approach in selected situations. Between May 2016 and December 2017, twenty-six transforaminal lumbar punctures were performed in 9 patients (25 CT-guided, 1 fluoroscopy-guided). Seven had spinal muscular atrophy and were referred for intrathecal nusinersen administration. In 2, CT myelography was performed via transforaminal lumbar puncture. The lumbar posterior elements were completely fused in 8, and there was an overlying abscess in 1...
May 2018: AJNR. American Journal of Neuroradiology
https://www.readbyqxmd.com/read/29560813/oligonucleotide-therapeutics-in-neurodegenerative-diseases
#13
Daniel R Scoles, Stefan M Pulst
Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2...
March 21, 2018: RNA Biology
https://www.readbyqxmd.com/read/29556256/spinal-muscular-atrophy-type-i-and-the-dual-role-of-viruses-an-interview-with-professor-basil-t-darras-professor-of-neurology-pediatrics-at-harvard-medical-school
#14
Ioannis N Mammas, Demetrios A Spandidos
According to Professor Basil T. Darras, Professor of Neurology (Pediatrics) at Harvard Medical School and Director of the Spinal Muscular Atrophy (SMA) Program at Boston Children's Hospital in Boston (MA, USA), the diagnosis of SMA type I is clinical and is based on detailed general physical and neurological examinations. SMA type I remains the most common genetic disease resulting in death in infancy and is really devastating for the child, the parents, as well as the medical professionals with the privilege of caring for patients with SMA and their parents...
April 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29549190/nusinersen-for-sma-expanded-access-programme
#15
Michelle A Farrar, Hooi Ling Teoh, Kate A Carey, Anita Cairns, Robin Forbes, Karen Herbert, Sandra Holland, Kristi J Jones, Manoj P Menezes, Margot Morrison, Kate Munro, Daniella Villano, Richard Webster, Ian R Woodcock, Eppie M Yiu, Hugo Sampaio, Monique M Ryan
BACKGROUND: Spinal muscular atrophy (SMA) is a devastating motor neuron disorder causing progressive muscle weakness and respiratory insufficiency. We present the initial Australian experiences implementing the expanded access programme (EAP) to enable preapproval access to nusinersen, the first disease-modifying therapy, for SMA type 1. METHODS: An Australian multicentre, open-label EAP for nusinersen enrolled patients with infantile-onset SMA type 1 from November 2016 to September 2017...
March 16, 2018: Journal of Neurology, Neurosurgery, and Psychiatry
https://www.readbyqxmd.com/read/29497154/motor-neuron-disease-benefits-of-nusinersen-extend-to-later-onset-sma
#16
Heather Wood
No abstract text is available yet for this article.
April 2018: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/29489501/prenatal-transplantation-of-human-amniotic-fluid-stem-cells-for-spinal-muscular-atrophy
#17
Shao-Yu Peng, Sheng-Wen S Shaw
PURPOSE OF REVIEW: To review the current medical and stem-cell therapy for spinal muscular atrophy (SMA) and prenatal transplantation of amniotic fluid stem cells in the future. RECENT FINDINGS: SMA is an autosomal recessive inheritance of neurodegenerative disease, which is caused of the mutation in survival motor neuron. The severe-type SMA patients usually die from the respiratory failure within 2 years after birth. Recently, researchers had found that 3-methyladenine could inhibit the autophagy and had the capacity to reduce death of the neurons...
April 2018: Current Opinion in Obstetrics & Gynecology
https://www.readbyqxmd.com/read/29478602/spinal-muscular-atrophy
#18
Eveline S Arnold, Kenneth H Fischbeck
Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg-Welander) is caused by mutation of the SMN1 gene, and the clinical severity correlates with the number of copies of a nearly identical gene, SMN2. The SMN protein plays a critical role in spliceosome assembly and may have other cellular functions, such as mRNA transport. Cell culture and animal models have helped to define the disease mechanism and to identify targets for therapeutic intervention. The main focus for developing treatment has been to increase SMN levels, and accomplishing this with small molecules, oligonucleotides, and gene replacement has been quite...
2018: Handbook of Clinical Neurology
https://www.readbyqxmd.com/read/29443664/nusinersen-versus-sham-control-in-later-onset-spinal-muscular-atrophy
#19
RANDOMIZED CONTROLLED TRIAL
Eugenio Mercuri, Basil T Darras, Claudia A Chiriboga, John W Day, Craig Campbell, Anne M Connolly, Susan T Iannaccone, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Perry B Shieh, Már Tulinius, Elena S Mazzone, Jacqueline Montes, Kathie M Bishop, Qingqing Yang, Richard Foster, Sarah Gheuens, C Frank Bennett, Wildon Farwell, Eugene Schneider, Darryl C De Vivo, Richard S Finkel
BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274...
February 15, 2018: New England Journal of Medicine
https://www.readbyqxmd.com/read/29434670/advances-in-spinal-muscular-atrophy-therapeutics
#20
REVIEW
Valeria Parente, Stefania Corti
Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families...
2018: Therapeutic Advances in Neurological Disorders
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