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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/28562381/respiratory-involvement-in-neuromuscular-disorders
#2
Matthias Boentert, Stephan Wenninger, Valeria A Sansone
PURPOSE OF REVIEW: In numerous neuromuscular disorders (NMDs), respiratory muscle weakness is present, and acute or chronic respiratory failure may evolve. Very often, respiratory involvement substantially adds to the burden of disease, impairs quality of life, or reduces life expectancy. This article summarizes new aspects of both diagnosis and management of respiratory muscle weakness in patients with NMDs. RECENT FINDINGS: Drugs like deflazacort, ataluren, eteplirsen, and nusinersen are now approved treatments for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy, and others are on their way in NMDs...
May 29, 2017: Current Opinion in Neurology
https://www.readbyqxmd.com/read/28561814/the-sma-trust-the-role-of-a-disease-focused-research-charity-in-developing-treatments-for-sma
#3
REVIEW
V Christie-Brown, J Mitchell, K Talbot
SMA is a rare hereditary neuromuscular disease that causes weakness and muscle wasting as a result of the loss of spinal motor neurons. In its most severe form, SMA is the commonest genetic cause of death in infants, and children with less severe forms of SMA face the prospect of lifelong disability from progressive muscle wasting, loss of mobility and limb weakness. The initial discovery of the defective gene has been followed by major advances in our understanding of the genetic, cellular and molecular basis of SMA, providing the foundation for a range of approaches to treatment including gene therapy, antisense oligonucleotide treatments and more traditional drug-based approaches to slow or halt disease progression...
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
#4
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/28556387/motor-milestone-assessment-of-infants-with-spinal-muscular-atrophy-using-the-hammersmith-infant-neurological-exam-part-2-experience-from-a-nusinersen-clinical-study
#5
Kathie M Bishop, Jacqueline Montes, Richard S Finkel
INTRODUCTION: We examined the feasibility of assessing motor milestone performance of infants with spinal muscular atrophy (SMA) using the Hammersmith Infant Neurological Exam - Part 2 (HINE-2) in a Phase 2 study of nusinersen. METHODS: Nineteen SMA infants were assessed using the HINE-2 at baseline (≤ 7 months of age), and periodically up to 39 months of age. We evaluated whether the HINE-2 was feasible, reliable, and sensitive to change. RESULTS: Motor milestone assessments in SMA infants were feasible using the HINE-2...
May 26, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28524214/-possible-treatments-for-infantile-spinal-atrophy
#6
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/28506401/plecanatide-nusinersen-and-obeticholic-acid
#7
Daniel A Hussar, Deborah K Douglas
No abstract text is available yet for this article.
May 2017: Journal of the American Pharmacists Association: JAPhA
https://www.readbyqxmd.com/read/28485722/how-the-discovery-of-iss-n1-led-to-the-first-medical-therapy-for-spinal-muscular-atrophy
#8
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/28467402/new-treatments-for-serious-conditions-ethical-implications
#9
REVIEW
N M P King, C E Bishop
Approval of Spinraza (nusinersen) for treatment of spinal muscular atrophy prompts consideration of a number of ethical issues that arise whenever a new treatment is proposed for a serious condition, especially one that is rare and can devastatingly affect children. Patients, families, clinicians, researchers, institutions and policymakers all must take account of the ways that newly available treatments affect informed and shared decision-making about therapeutic and research options. The issues to consider include: addressing what is still uncertain and unknown; the possibility that potential benefits will be exaggerated and potential harms underemphasized in the media, by advocacy organizations, and in consent forms and processes; the high cost of many novel drugs and biologics; the effects of including conditions of variable phenotype in state-mandated newborn screening panels; and how new treatments can change the standard of care, altering what is and is not known about a disorder and posing challenges for decision-making at both individual and policy levels...
May 11, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28400976/iss-n1-makes-the-first-fda-approved-drug-for-spinal-muscular-atrophy
#10
Eric W Ottesen
Spinal muscular atrophy (SMA) is one of the leading genetic diseases of children and infants. SMA is caused by deletions or mutations of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, cannot compensate for the loss of SMN1 due to predominant skipping of exon 7. While various regulatory elements that modulate SMN2 exon 7 splicing have been proposed, intronic splicing silencer N1 (ISS-N1) has emerged as the most promising target thus far for antisense oligonucleotide-mediated splicing correction in SMA...
January 2017: Translational Neuroscience
https://www.readbyqxmd.com/read/28369979/population-pharmacokinetics-of-nusinersen-in-the-cerebral-spinal-fluid-and-plasma-of-pediatric-patients-with-spinal-muscular-atrophy-following-intrathecal-administrations
#11
Kenneth T Luu, Daniel A Norris, Rudy Gunawan, Scott Henry, Richard Geary, Yanfeng Wang
Nusinersen is an antisense oligonucleotide intended for the treatment of spinal muscular atrophy. The pharmacokinetics of nusinersen, following intrathecal administrations, in the cerebrospinal fluid (CSF) and plasma of 72 pediatric patients (3 months to 17 years) with spinal muscular atrophy across 5 clinical trials was analyzed via population-based modeling. With sparse data in the CSF and profile data in the plasma, a linear 4-compartment model simultaneously described the time-concentration profiles in both matrices...
March 29, 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28346110/fda-approval-of-nusinersen-for-spinal-muscular-atrophy-makes-2016-the-year-of-splice-modulating-oligonucleotides
#12
Annemieke Aartsma-Rus
No abstract text is available yet for this article.
April 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28323809/nusinersen-spinraza-for-spinal-muscular-atrophy
#13
(no author information available yet)
No abstract text is available yet for this article.
March 27, 2017: Medical Letter on Drugs and Therapeutics
https://www.readbyqxmd.com/read/28250698/pharmaceutical-approval-update
#14
Mary Choy
Insulin degludec/liraglutide (Xultophy 100/3.6) for type-2 diabetes; rucaparib (Rubraca) for the treatment of deleterious BRCA mutation-associated ovarian cancer; and nusinersen (Spinraza) for the treatment of spinal muscular atrophy.
March 2017: P & T: a Peer-reviewed Journal for Formulary Management
https://www.readbyqxmd.com/read/28244991/oligonucleotide-therapies-for-disorders-of-the-nervous-system
#15
Olga Khorkova, Claes Wahlestedt
Oligonucleotide therapies are currently experiencing a resurgence driven by advances in backbone chemistry and discoveries of novel therapeutic pathways that can be uniquely and efficiently modulated by the oligonucleotide drugs. A quarter of a century has passed since oligonucleotides were first applied in living mammalian brain to modulate gene expression. Despite challenges in delivery to the brain, multiple oligonucleotide-based compounds are now being developed for treatment of human brain disorders by direct delivery inside the blood brain barrier (BBB)...
March 2017: Nature Biotechnology
https://www.readbyqxmd.com/read/28229309/nusinersen-first-global-approval
#16
REVIEW
Sheridan M Hoy
Spinal muscular atrophy (SMA) is a rare autosomal recessive disorder characterized by muscle atrophy and weakness resulting from motor neuron degeneration in the spinal cord and brainstem. It is most commonly caused by insufficient levels of survival motor neuron (SMN) protein (which is critical for motor neuron maintenance) secondary to deletions or mutations in the SMN1 gene. Nusinersen (SPINRAZA™) is a modified antisense oligonucleotide that binds to a specific sequence in the intron, downstream of exon 7 on the pre-messenger ribonucleic acid (pre-mRNA) of the SMN2 gene...
March 2017: Drugs
https://www.readbyqxmd.com/read/28192393/nusinersen-an-antisense-oligonucleotide-drug-for-spinal-muscular-atrophy
#17
David R Corey
No abstract text is available yet for this article.
February 13, 2017: Nature Neuroscience
https://www.readbyqxmd.com/read/28009016/motor-neuron-disease-nusinersen-potentially-effective-in-sma
#18
Louise Adams
No abstract text is available yet for this article.
February 2017: Nature Reviews. Neurology
https://www.readbyqxmd.com/read/27939059/treatment-of-infantile-onset-spinal-muscular-atrophy-with-nusinersen-a-phase-2-open-label-dose-escalation-study
#19
Richard S Finkel, Claudia A Chiriboga, Jiri Vajsar, John W Day, Jacqueline Montes, Darryl C De Vivo, Mason Yamashita, Frank Rigo, Gene Hung, Eugene Schneider, Daniel A Norris, Shuting Xia, C Frank Bennett, Kathie M Bishop
BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy. Nusinersen is specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the amount of functional survival motor neuron (SMN) protein that is deficient in patients with spinal muscular atrophy. METHODS: This open-label, phase 2, escalating dose clinical study assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy...
December 17, 2016: Lancet
https://www.readbyqxmd.com/read/26865511/results-from-a-phase-1-study-of-nusinersen-isis-smn-rx-in-children-with-spinal-muscular-atrophy
#20
MULTICENTER STUDY
Claudia A Chiriboga, Kathryn J Swoboda, Basil T Darras, Susan T Iannaccone, Jacqueline Montes, Darryl C De Vivo, Daniel A Norris, C Frank Bennett, Kathie M Bishop
OBJECTIVE: To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA). METHODS: Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants...
March 8, 2016: Neurology
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