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[PMID]:28463817
[Au] Autor:Zheng C; Zhu Y; Zhu D; Lu F; Xia X; Jiang J; Ma X
[Ad] Endereço:Department of Orthopedics, Huashan Hospital, Fudan University, Shanghai 200040, China.
[Ti] Título:Motor unit number estimation in the quantitative assessment of severity and progression of motor unit loss in Hirayama disease.
[So] Source:Clin Neurophysiol;128(6):1008-1014, 2017 06.
[Is] ISSN:1872-8952
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:OBJECTIVE: To investigate motor unit number estimation (MUNE) as a method to quantitatively evaluate severity and progression of motor unit loss in Hirayama disease (HD). METHODS: Multipoint incremental MUNE was performed bilaterally on both abductor digiti minimi and abductor pollicis brevis muscles in 46 patients with HD and 32 controls, along with handgrip strength examination. MUNE was re-evaluated approximately 1year after initial examination in 17 patients with HD. RESULTS: The MUNE values were significantly lower in all the tested muscles in the HD group (P<0.05). Despite abnormally low MUNE values, 54.3% (25/46) of patients with HD had normal ipsilateral grip power. There was a significant inverse correlation between MUNE values and disease duration (P<0.05). A longitudinal follow-up MUNE analysis demonstrated slow progression of motor unit loss in patients with HD within approximately 1year (P<0.05), even in patients with an illness duration >4years. CONCLUSIONS: A reduction in the functioning motor units was found in patients with HD compared with that in controls, even in the early asymptomatic stages. Moreover, the motor unit loss in HD progresses gradually as the disease advances. SIGNIFICANCE: These results have provided evidence for the application of MUNE in estimating the reduction of motor unit in HD and confirming the validity of MUNE for tracking the progression of HD in a clinical setting.
[Mh] Termos MeSH primário: Força da Mão
Nervo Mediano/fisiopatologia
Músculo Esquelético/fisiopatologia
Atrofias Musculares Espinais da Infância/fisiopatologia
Nervo Ulnar/fisiopatologia
[Mh] Termos MeSH secundário: Adolescente
Adulto
Estudos de Casos e Controles
Progressão da Doença
Eletromiografia/métodos
Seres Humanos
Músculo Esquelético/inervação
Atrofias Musculares Espinais da Infância/diagnóstico
[Pt] Tipo de publicação:EVALUATION STUDIES; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Em] Mês de entrada:1708
[Cu] Atualização por classe:180306
[Lr] Data última revisão:
180306
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE


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[PMID]:29443664
[Au] Autor:Mercuri E; Darras BT; Chiriboga CA; Day JW; Campbell C; Connolly AM; Iannaccone ST; Kirschner J; Kuntz NL; Saito K; Shieh PB; Tulinius M; Mazzone ES; Montes J; Bishop KM; Yang Q; Foster R; Gheuens S; Bennett CF; Farwell W; Schneider E; De Vivo DC; Finkel RS; CHERISH Study Group
[Ad] Endereço:From the Department of Pediatric Neurology, Catholic University, Rome (E.M., E.S.M.); the Department of Neurology, Boston Children's Hospital, Boston (B.T.D.), and Biogen, Cambridge (R.F., S.G., W.F.) - both in Massachusetts; the Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D
[Ti] Título:Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy.
[So] Source:N Engl J Med;378(7):625-635, 2018 02 15.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. RESULTS: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .).
[Mh] Termos MeSH primário: Oligonucleotídeos Antissenso/uso terapêutico
Oligonucleotídeos/uso terapêutico
Atrofias Musculares Espinais da Infância/tratamento farmacológico
[Mh] Termos MeSH secundário: Idade de Início
Criança
Pré-Escolar
Método Duplo-Cego
Feminino
Seres Humanos
Lactente
Injeções Espinhais
Análise dos Mínimos Quadrados
Masculino
Destreza Motora
Oligonucleotídeos/efeitos adversos
Oligonucleotídeos Antissenso/efeitos adversos
Atrofias Musculares Espinais da Infância/fisiopatologia
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; COMPARATIVE STUDY; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Oligonucleotides); 0 (Oligonucleotides, Antisense); 0 (nusinersen)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180215
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1710504


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[PMID]:29394306
[Au] Autor:Whittaker HT; Michell-Robinson MA
[Ad] Endereço:McGill University Faculty of Medicine, Montreal, Canada
[Ti] Título:Therapy for Spinal Muscular Atrophy.
[So] Source:N Engl J Med;378(5):487, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Atrofia Muscular Espinal
Atrofias Musculares Espinais da Infância
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:LETTER; COMMENT
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1715769


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[PMID]:29394473
[Au] Autor:Mendell JR
[Ad] Endereço:Nationwide Children's Hospital, Columbus, OH jerry.mendell@nationwidechildrens.org
[Ti] Título:Therapy for Spinal Muscular Atrophy.
[So] Source:N Engl J Med;378(5):487, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Atrofia Muscular Espinal
Atrofias Musculares Espinais da Infância
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:LETTER; COMMENT
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180203
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1715769


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[PMID]:29385371
[Au] Autor:Finkel RS; Farwell W
[Ad] Endereço:Nemours Children's Hospital, Orlando, FL richard.finkel@nemours.org
[Ti] Título:Therapy for Spinal Muscular Atrophy.
[So] Source:N Engl J Med;378(5):487-488, 2018 02 01.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Atrofia Muscular Espinal
Atrofias Musculares Espinais da Infância
[Mh] Termos MeSH secundário: Seres Humanos
[Pt] Tipo de publicação:LETTER; COMMENT
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180207
[Lr] Data última revisão:
180207
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:180201
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMc1715769


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[PMID]:28460889
[Au] Autor:Bertini E; Dessaud E; Mercuri E; Muntoni F; Kirschner J; Reid C; Lusakowska A; Comi GP; Cuisset JM; Abitbol JL; Scherrer B; Ducray PS; Buchbjerg J; Vianna E; van der Pol WL; Vuillerot C; Blaettler T; Fontoura P; Olesoxime SMA Phase 2 Study Investigators
[Ad] Endereço:Department of Neurosciences and Neurorehabilitation, Bambino Gesù Children's Research Hospital IRCCS, Rome, Italy. Electronic address: enricosilvio.bertini@opbg.net.
[Ti] Título:Safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 spinal muscular atrophy: a randomised, double-blind, placebo-controlled phase 2 trial.
[So] Source:Lancet Neurol;16(7):513-522, 2017 Jul.
[Is] ISSN:1474-4465
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Spinal muscular atrophy (SMA) is a progressive motor neuron disease causing loss of motor function and reduced life expectancy, for which limited treatment is available. We investigated the safety and efficacy of olesoxime in patients with type 2 or non-ambulatory type 3 SMA. METHODS: This randomised, double-blind, placebo-controlled, phase 2 study was done in 22 neuromuscular care centres in Belgium, France, Germany, Italy, Netherlands, Poland, and the UK. Safety and efficacy of olesoxime were assessed in patients aged 3-25 years with genetically confirmed type 2 or non-ambulatory type 3 SMA. A centralised, computerised randomisation process allocated patients (2:1 with stratification by SMA type and centre) to receive olesoxime (10 mg/kg per day) in an oral liquid suspension or placebo for 24 months. Patients, investigators assessing outcomes, and sponsor study personnel were masked to treatment assignment. The primary outcome measure was change from baseline compared with 24 months between the two treatment groups in functional domains 1 and 2 of the Motor Function Measure (MFM D1 + D2) assessed in the full analysis population. A shorter, 20-item version of the MFM, which was specifically adapted for young children, was used to assess patients younger than 6 years. Safety was assessed in all patients who received one or more doses of the study drug. The trial is registered with ClinicalTrials.gov, number NCT01302600. FINDINGS: The trial was done between Nov 18, 2010, and Oct 9, 2013. Of 198 patients screened, 165 were randomly assigned to olesoxime (n=108) or placebo (n=57). Five patients in the olesoxime group were not included in the primary outcome analysis because of an absence of post-baseline assessments. The change from baseline to month 24 on the primary outcome measure was 0·18 for olesoxime and -1·82 for placebo (treatment difference 2·00 points, 96% CI -0·25 to 4·25, p=0·0676). Olesoxime seemed to be safe and generally well tolerated, with an adverse event profile similar to placebo. The most frequent adverse events in the olesoxime group were pyrexia (n=34), cough (n=32), nasopharyngitis (n=25), and vomiting (n=25). There were two patient deaths (one in each group), but these were not deemed to be related to the study treatment. INTERPRETATION: Olesoxime was safe at the doses studied, for the duration of the trial. Although the primary endpoint was not met, secondary endpoints and sensitivity analyses suggest that olesoxime might maintain motor function in patients with type 2 or type 3 SMA over a period of 24 months. Based on these results, olesoxime might provide meaningful clinical benefits for patients with SMA and, given its mode of action, might be used in combination with other drugs targeting other mechanisms of disease, although additional evidence is needed. FUNDING: AFM Téléthon and Trophos SA.
[Mh] Termos MeSH primário: Colestenonas/farmacologia
Fármacos Neuroprotetores/farmacologia
Avaliação de Resultados (Cuidados de Saúde)
Atrofias Musculares Espinais da Infância/tratamento farmacológico
[Mh] Termos MeSH secundário: Adolescente
Adulto
Criança
Pré-Escolar
Colestenonas/administração & dosagem
Colestenonas/efeitos adversos
Método Duplo-Cego
Feminino
Seres Humanos
Masculino
Limitação da Mobilidade
Fármacos Neuroprotetores/administração & dosagem
Fármacos Neuroprotetores/efeitos adversos
Atrofias Musculares Espinais da Infância/fisiopatologia
Adulto Jovem
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Cholestenones); 0 (Neuroprotective Agents); A6778U5IFY (olesoxime)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:180121
[Lr] Data última revisão:
180121
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE


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[PMID]:29188975
[Au] Autor:Sätilä H; Lähdesmäki J; Mäkelä E; Kähärä V; Hietaharju A
[Ti] Título:Hirayama disease.
[So] Source:Duodecim;132(19):1797-803, 2016.
[Is] ISSN:0012-7183
[Cp] País de publicação:Finland
[La] Idioma:eng
[Ab] Resumo:Hirayama is a form of cervical myelopathy affecting mainly young men. The cardinal features include progressive, either symmetrical or asymmetrical muscular weakness and atrophy of muscles innervated by C7-Th1 motoneurons. The application of soft daytime collar during the early stage of illness can halt the progression of illness.
[Mh] Termos MeSH primário: Equipamentos Ortopédicos
Atrofias Musculares Espinais da Infância/diagnóstico
Atrofias Musculares Espinais da Infância/terapia
[Mh] Termos MeSH secundário: Adolescente
Diagnóstico Diferencial
Progressão da Doença
Seres Humanos
Imagem por Ressonância Magnética
Masculino
[Pt] Tipo de publicação:CASE REPORTS; JOURNAL ARTICLE
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180108
[Lr] Data última revisão:
180108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171201
[St] Status:MEDLINE


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[PMID]:29091570
[Au] Autor:Finkel RS; Mercuri E; Darras BT; Connolly AM; Kuntz NL; Kirschner J; Chiriboga CA; Saito K; Servais L; Tizzano E; Topaloglu H; Tulinius M; Montes J; Glanzman AM; Bishop K; Zhong ZJ; Gheuens S; Bennett CF; Schneider E; Farwell W; De Vivo DC; ENDEAR Study Group
[Ad] Endereço:From the Division of Neurology, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL (R.S.F.); the Department of Pediatric Neurology, Catholic University, Rome (E.M.); the Department of Neurology, Boston Children's Hospital, Boston (B.T.D.), and Biogen, Cambridge (Z.J.Z., S.G., W.F.) -
[Ti] Título:Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy.
[So] Source:N Engl J Med;377(18):1723-1732, 2017 11 02.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo: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. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis. RESULTS: In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups. CONCLUSIONS: Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
[Mh] Termos MeSH primário: Oligonucleotídeos Antissenso/uso terapêutico
Oligonucleotídeos/uso terapêutico
Atrofias Musculares Espinais da Infância/tratamento farmacológico
[Mh] Termos MeSH secundário: Idade de Início
Intervalo Livre de Doença
Método Duplo-Cego
Feminino
Seres Humanos
Lactente
Injeções Espinhais
Masculino
Destreza Motora
Oligonucleotídeos/efeitos adversos
Oligonucleotídeos Antissenso/efeitos adversos
RNA Mensageiro/efeitos dos fármacos
RNA Mensageiro/metabolismo
Respiração Artificial
Atrofias Musculares Espinais da Infância/genética
Atrofias Musculares Espinais da Infância/mortalidade
Atrofias Musculares Espinais da Infância/fisiopatologia
Análise de Sobrevida
Proteína 2 de Sobrevivência do Neurônio Motor/genética
Proteína 2 de Sobrevivência do Neurônio Motor/metabolismo
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE III; JOURNAL ARTICLE; MULTICENTER STUDY; RANDOMIZED CONTROLLED TRIAL
[Nm] Nome de substância:
0 (Oligonucleotides); 0 (Oligonucleotides, Antisense); 0 (RNA, Messenger); 0 (Survival of Motor Neuron 2 Protein); 0 (nusinersen)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171102
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1702752


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[PMID]:29091557
[Au] Autor:Mendell JR; Al-Zaidy S; Shell R; Arnold WD; Rodino-Klapac LR; Prior TW; Lowes L; Alfano L; Berry K; Church K; Kissel JT; Nagendran S; L'Italien J; Sproule DM; Wells C; Cardenas JA; Heitzer MD; Kaspar A; Corcoran S; Braun L; Likhite S; Miranda C; Meyer K; Foust KD; Burghes AHM; Kaspar BK
[Ad] Endereço:From the Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital (J.R.M., S.A.-Z., L.R.R.-K., L.L., L.A., K.B., K.C., S.L., C.M., K.M., B.K.K.) and the Departments of Pediatrics (J.R.M., S.A.-Z., R.S., L.L., L.A., K.B., K.C., J.T.K., B.K.K.), Neurology (J.R.M., W.D.A., L.
[Ti] Título:Single-Dose Gene-Replacement Therapy for Spinal Muscular Atrophy.
[So] Source:N Engl J Med;377(18):1713-1722, 2017 11 02.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:BACKGROUND: Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve motor milestones and in death or the need for mechanical ventilation by 2 years of age. We studied functional replacement of the mutated gene encoding survival motor neuron 1 (SMN1) in this disease. METHODS: Fifteen patients with SMA1 received a single dose of intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA encoding the missing SMN protein. Three of the patients received a low dose (6.7×10 vg per kilogram of body weight), and 12 received a high dose (2.0×10 vg per kilogram). The primary outcome was safety. The secondary outcome was the time until death or the need for permanent ventilatory assistance. In exploratory analyses, we compared scores on the CHOP INTEND (Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders) scale of motor function (ranging from 0 to 64, with higher scores indicating better function) in the two cohorts and motor milestones in the high-dose cohort with scores in studies of the natural history of the disease (historical cohorts). RESULTS: As of the data cutoff on August 7, 2017, all 15 patients were alive and event-free at 20 months of age, as compared with a rate of survival of 8% in a historical cohort. In the high-dose cohort, a rapid increase from baseline in the score on the CHOP INTEND scale followed gene delivery, with an increase of 9.8 points at 1 month and 15.4 points at 3 months, as compared with a decline in this score in a historical cohort. Of the 12 patients who had received the high dose, 11 sat unassisted, 9 rolled over, 11 fed orally and could speak, and 2 walked independently. Elevated serum aminotransferase levels occurred in 4 patients and were attenuated by prednisolone. CONCLUSIONS: In patients with SMA1, a single intravenous infusion of adeno-associated viral vector containing DNA coding for SMN resulted in longer survival, superior achievement of motor milestones, and better motor function than in historical cohorts. Further studies are necessary to confirm the safety and efficacy of this gene therapy. (Funded by AveXis and others; ClinicalTrials.gov number, NCT02122952 .).
[Mh] Termos MeSH primário: Terapia Genética
Atrofias Musculares Espinais da Infância/terapia
Proteína 1 de Sobrevivência do Neurônio Motor/genética
[Mh] Termos MeSH secundário: Estudos de Coortes
Dependovirus
Intervalo Livre de Doença
Feminino
Terapia Genética/efeitos adversos
Vetores Genéticos
Estudo Historicamente Controlado
Seres Humanos
Lactente
Recém-Nascido
Infusões Intravenosas
Hepatopatias/etiologia
Masculino
Destreza Motora
Apoio Nutricional
Respiração Artificial
Atrofias Musculares Espinais da Infância/genética
Atrofias Musculares Espinais da Infância/fisiopatologia
[Pt] Tipo de publicação:CLINICAL TRIAL, PHASE I; CLINICAL TRIAL, PHASE II; CONTROLLED CLINICAL TRIAL; JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Survival of Motor Neuron 1 Protein)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171109
[Lr] Data última revisão:
171109
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:171102
[Cl] Clinical Trial:ClinicalTrial
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMoa1706198


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[PMID]:28799578
[Au] Autor:Paton DM
[Ad] Endereço:University of Auckland School of Medical Sciences, Pharmacology & Clinical Pharmacology, Auckland, New Zealand. dmpaton38@yahoo.ca.
[Ti] Título:Nusinersen: antisense oligonucleotide to increase SMN protein production in spinal muscular atrophy.
[So] Source:Drugs Today (Barc);53(6):327-337, 2017 Jun.
[Is] ISSN:1699-3993
[Cp] País de publicação:Spain
[La] Idioma:eng
[Ab] Resumo: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. On a dose basis, nusinersen was found to be the most potent ASO for SMN2 splicing correction in the CNS of adult mice. After nusinersen was found to increase levels of SMN protein in the CNS of mice and subhuman primates without causing significant adverse events, it was advanced into clinical studies in patients with SMA. These trials in SMA patients have demonstrated significant improvements in various measures of motor function and in progression to movement developments not normally seen in SMA patients. In addition, there have been significant extensions in life expectancy. These findings led to the U.S. and European approval of nusinersen for use in SMA patients of all ages.
[Mh] Termos MeSH primário: Processamento Alternativo/efeitos dos fármacos
Oligonucleotídeos Antissenso/uso terapêutico
Oligonucleotídeos/uso terapêutico
Atrofias Musculares Espinais da Infância/terapia
[Mh] Termos MeSH secundário: Adulto
Processamento Alternativo/genética
Animais
Sistema Nervoso Central/metabolismo
Ensaios Clínicos como Assunto
Avaliação Pré-Clínica de Medicamentos
Éxons
Dosagem de Genes
Haplorrinos
Seres Humanos
Lactente
Injeções Espinhais
Nefropatias/induzido quimicamente
Camundongos
Estudos Multicêntricos como Assunto
Oligonucleotídeos/administração & dosagem
Oligonucleotídeos/efeitos adversos
Oligonucleotídeos/farmacocinética
Oligonucleotídeos Antissenso/administração & dosagem
Oligonucleotídeos Antissenso/efeitos adversos
Oligonucleotídeos Antissenso/farmacocinética
Estabilidade Proteica
Atrofias Musculares Espinais da Infância/genética
Proteína 1 de Sobrevivência do Neurônio Motor/genética
Proteína 2 de Sobrevivência do Neurônio Motor/biossíntese
Proteína 2 de Sobrevivência do Neurônio Motor/genética
Tionucleotídeos/administração & dosagem
Tionucleotídeos/efeitos adversos
Tionucleotídeos/farmacocinética
Tionucleotídeos/uso terapêutico
Trombocitopenia/induzido quimicamente
Regulação para Cima/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Oligonucleotides); 0 (Oligonucleotides, Antisense); 0 (SMN1 protein, human); 0 (SMN2 protein, human); 0 (SMN2 protein, mouse); 0 (Survival of Motor Neuron 1 Protein); 0 (Survival of Motor Neuron 2 Protein); 0 (Thionucleotides); 0 (nusinersen)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170812
[St] Status:MEDLINE
[do] DOI:10.1358/dot.2017.53.6.2652413



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