***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: 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 r and omly 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 – Exp and ed ( 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 clinical ly 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 clinical ly meaningful improvement in motor function as compared with those in the control group . ( Funded by Biogen and Ionis Pharmaceuticals ; CHERISH Clinical Trials.gov number , NCT02292537 . 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 r and omized , 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 Clinical Trials.gov number , NCT02193074 . Objective : To examine safety , tolerability , pharmacokinetics , and preliminary clinical efficacy of intrathecal nusinersen ( previously ISIS-SMNRx ) , an antisense oligonucleotide design ed 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 . Participants were monitored for safety and tolerability , and CSF and plasma pharmacokinetics were measured . Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Exp and ed ( HFMSE ) and Pediatric Quality of Life Inventory . Results : A total of 28 participants enrolled in the study ( n = 6 in first 3 dose cohorts ; n = 10 in the 9-mg cohort ) . Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified . Plasma and CSF drug levels were dose-dependent , consistent with pre clinical data . Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4–6 months after initial clearance . A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose ( 3.1 points ; p = 0.016 ) , which was further increased 9–14 months postdose ( 5.8 points ; p = 0.008 ) during the extension study . Conclusions : Results from this study support continued development of nusinersen for treatment of SMA . Classification of evidence : This study provides Class IV evidence that in children with SMA , intrathecal nusinersen is not associated with safety or tolerability concerns Nusinersen ( ISIS-SMNRx or ISIS 396443 ) is an antisense oligonucleotide drug administered intrathecally to treat spinal muscular atrophy . We summarize lumbar puncture experience in children with spinal muscular atrophy during a phase 1 open-label study of nusinersen and its extension . During the studies , 73 lumbar punctures were performed in 28 patients 2 to 14 years of age with type 2/3 spinal muscular atrophy .  No complications occurred in 50 ( 68 % ) lumbar punctures ; in 23 ( 32 % ) procedures , adverse events were attributed to lumbar puncture . Most common adverse events were headache ( n = 9 ) , back pain ( n = 9 ) , and post – lumbar puncture syndrome ( n = 8) . In a subgroup analysis , adverse events were more frequent in older children , children with type 3 spinal muscular atrophy , and with a 21- or 22-gauge needle compared to a 24-gauge needle or smaller . Lumbar punctures were successfully performed in children with spinal muscular atrophy ; lumbar puncture – related adverse event frequency was similar to that previously reported in children Objectives : Prospect i ve cohort study to characterize the clinical features and course of spinal muscular atrophy type I ( SMA-I ) . Methods : Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical , motor function , laboratory , and electrophysiologic outcome assessment s. Intervention was determined by published st and ard of care guidelines . Palliative care options were offered . Results : Thirty-four of 54 eligible subjects with SMA-I ( 63 % ) enrolled and 50 % of these completed at least 12 months of follow-up . The median age at reaching the combined endpoint of death or requiring at least 16 hours/day of ventilation support was 13.5 months ( interquartile range 8.1–22.0 months ) . Requirement for nutritional support preceded that for ventilation support . The distribution of age at reaching the combined endpoint was similar for subjects with SMA-I who had symptom onset before 3 months and after 3 months of age ( p = 0.58 ) . Having 2 SMN2 copies was associated with greater morbidity and mortality than having 3 copies . Baseline electrophysiologic measures indicated substantial motor neuron loss . By comparison , subjects with SMA-II who lost sitting ability ( n = 10 ) had higher motor function , motor unit number estimate and compound motor action potential , longer survival , and later age when feeding or ventilation support was required . The mean rate of decline in The Children 's Hospital of Philadelphia Infant Test for Neuromuscular Disorders motor function scale was 1.27 points/year ( 95 % confidence interval 0.21–2.33 , p = 0.02 ) . Conclusions : Infants with SMA-I can be effectively enrolled and retained in a 12-month natural history study until a majority reach the combined endpoint . These outcome data can be used for clinical trial design BACKGROUND Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified antisense drug being developed to treat spinal muscular atrophy .  Nusinersen is specifically design ed 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 . Eligible participants were of either gender aged between 3 weeks and 7 months old with onset of spinal muscular atrophy symptoms between 3 weeks and 6 months , who had SMN1 homozygous gene deletion or mutation . Safety assessment s included adverse events , physical and neurological examinations , vital signs , clinical laboratory tests , cerebrospinal fluid laboratory tests , and electrocardiographs . Clinical efficacy assessment s included event free survival , and change from baseline of two assessment s of motor function : the motor milestones portion of the Hammersmith Infant Neurological Exam-Part 2 ( HINE-2 ) and the Children 's Hospital of Philadelphia Infant Test of Neuromuscular Disorders ( CHOP-INTEND ) motor function test , and compound motor action potentials . Autopsy tissue was analysed for target engagement , drug concentrations , and pharmacological activity . HINE-2 , CHOP-INTEND , and compound motor action potential were compared between baseline and last visit using the Wilcoxon signed-rank test . Age at death or permanent ventilation was compared with natural history using the log-rank test . The study is registered at Clinical Trials.gov , number NCT01839656 . FINDINGS 20 participants were enrolled between May 3 , 2013 , and July 9 , 2014 , and assessed through to an interim analysis done on Jan 26 , 2016 . All participants experienced adverse events , with 77 serious adverse events reported in 16 participants , all considered by study investigators not related or unlikely related to the study drug . In the 12 mg dose group , incremental achievements of motor milestones ( p<0·0001 ) , improvements in CHOP-INTEND motor function scores ( p=0·0013 ) , and increased compound muscle action potential amplitude of the ulnar nerve ( p=0·0103 ) and peroneal nerve ( p<0·0001 ) , compared with baseline , were observed . Median age at death or permanent ventilation was not reached and the Kaplan-Meier survival curve diverged from a published natural history case series ( p=0·0014 ) . Analysis of autopsy tissue from patients exposed to nusinersen showed drug uptake into motor neurons throughout the spinal cord and neurons and other cell types in the brainstem and other brain regions , exposure at therapeutic concentrations , and increased SMN2 mRNA exon 7 inclusion and SMN protein concentrations in the spinal cord . INTERPRETATION Administration of multiple intrathecal doses of nusinersen showed acceptable safety and tolerability , pharmacology consistent with its intended mechanism of action , and encouraging clinical efficacy . Results informed the design of an ongoing , sham-controlled , phase 3 clinical study of nusinersen in infantile-onset spinal muscular atro 
    Output:
    
Results of these trials are hopeful with significant and clinical ly meaningful improvement due to treatment with intrathecal nusinersen in patients with early- and later-onset spinal muscular atrophy , although this does not restore age-appropriate function .
Intrathecal nusinersen has acceptable safety and tolerability .