Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Mercuri, Eugenio; Darras, Basil T.; Chiriboga, Claudia A.; Day, John W.; Campbell, Craig; Connolly, Anne M.; Iannaccone, Susan T.; Kirschner, Janbernd; Kuntz, Nancy L.; Saito, Kayoko; Shieh, Perry B.; Tulinius, M.; Mazzone, Elena; Montes, Jacqueline; Bishop, Kathie M.; Yang, Qingqing; Foster, Richard; Gheuens, Sarah; Bennett, C. Frank; Farwell, Wildon; Schneider, Eugene; Vivo, Darryl C. De; Finkel, Richard S.

doi:10.1056/nejmoa1710504

Cited by 1,095 publications

(1,060 citation statements)

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“…More specifically, we wished (1) to establish if the data in the infants assessed below the age of 7 months (210 days) were consistent with the ENDEAR study; (2) to assess whether there was any improvement in older children and, if present, if this was related to age, severity, or number of SMN2 copies; and (3) to determine if longer followup would help to better define the magnitude of changes. Finally, we also aimed to establish, using dedicated patientreported questionnaires, whether possible improvements on the functional scales were related to the caregivers' perception of clinically meaningful improvements.…”

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Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

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Sansone

et al. 2019

Annals of Neurology

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Objective: The aim of the study was to report 12-month changes after treatment with nusinersen in a cohort of 85 type I spinal muscular atrophy patients of ages ranging from 2 months to 15 years and 11 months. Methods: All patients were assessed using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination-Section 2 (HINE-2). Results: Two of the 85 patients had 1 SMN2 copy, 61 had 2 copies, and 18 had 3 copies. In 4 patients the SMN2 copy number was not available. At baseline, the mean CHOP INTEND scores ranged between 0 and 52 (mean = 15.66, standard deviation [SD] = AE13.48), and the mean HINE-2 score was between 0 and 5 (mean = 0.69, SD = AE1.23). There was a difference between baseline and the 12-month scores on both the CHOP INTEND and the HINE-2 for the whole group (p < 0.001), the subgroups with 2 SMN2 copies (p < 0.001), and those with 3 SMN2 copies (p < 0.001). The difference was found not only in patients younger than 210 days at baseline (p < 0.001) but also in those younger than 5 years on the CHOP INTEND and younger than 2 years on the HINE-2. Interpretation: Our results, expanding the age range and the severity of type I patients treated with nusinersen over 1 year, provide additional data on the range of efficacy of the drug that will be helpful in making an informed decision on whether to start treatment in patients of different ages and severity.

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Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

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Coratti

Sansone

et al. 2019

Annals of Neurology

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“…In September 2015, the first patients were dosed in a human trial of a huntingtin‐lowering ASO drug (NCT02519036). HTT Rx was developed by Ionis Pharmaceuticals, for whom the past decade also encompasses a notable name change from Isis, and successes including dramatic therapeutic rescue using an ASO in children with spinal muscular atrophy and, most recently, impressive preliminary results in familial amyotrophic lateral sclerosis . In the first human trial of HTT Rx , 46 patients received 4 doses or placebo by intrathecal injection at monthly intervals in a multiple‐ascending‐dose design.…”

Section: The Third Age Of Huntington's Disease?mentioning

confidence: 99%

One decade ago, one decade ahead in huntington's disease

Wild

Tabrizi

2019

Movement Disorders

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“…Antisense oligonucleotide (ASO)‐based therapies have recently garnered enormous interest propelled by U.S. Food and Drug Administration (FDA) approval of three ASOs . ASOs are short, synthetic, single‐stranded nucleic acids.…”

Section: Aso Therapeutics For Neurodegenerative Diseasementioning

confidence: 99%

“…Therapeutic ASOs are typically ∼20 base pair (bp) oligonucleotides in length, but can range to more than 30 bp. They modify the expression of a target mRNA, either by altering splicing (exon skipping or exon inclusion), by recruiting RNase H leading to target degradation, or by interfering with translation, with the mode of action depending on the target sequence and the ASO chemistry . Additional details regarding ASO base and backbone chemical modifications for a desired mechanism of action are provided below.…”

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confidence: 99%

Antisense therapies for movement disorders

Scoles

Pulst

2019

Movement Disorders

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Currently, few disease‐modifying therapies exist for degenerative movement disorders. Antisense oligonucleotides are small DNA oligonucleotides, usually encompassing ∼20 base pairs, that can potentially target any messenger RNA of interest. Antisense oligonucleotides often contain modifications to the phosphate backbone, the sugar moiety, and the nucleotide base. The development of antisense oligonucleotide therapies spinal muscular atrophy and Duchenne muscular dystrophy suggest potentially wide‐ranging therapeutic applications for antisense oligonucleotides in neurology. Successes with these two diseases have heightened interest in academia and the pharmaceutical industry to develop antisense oligonucleotides for several movement disorders, including, spinocerebellar ataxias, Huntington's disease, and Parkinson's disease. Compared to small molecules, antisense oligonucleotide–based therapies have an advantage because the target disease gene sequence is the immediate path to identifying the therapeutically effective complementary antisense oligonucleotide. In this review we describe the different types of antisense oligonucleotide chemistries and their potential use for the treatment of human movement disorders. © 2019 International Parkinson and Movement Disorder Society

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Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Abstract: 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 .).

Cited by 1,095 publications

References 35 publications

Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

One decade ago, one decade ahead in huntington's disease

Antisense therapies for movement disorders

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