***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: The US National Institute of Neurological Disorders and Stroke convened major stakeholders in June 2012 to discuss how to improve the method ological reporting of animal studies in grant applications and publications . The main workshop recommendation is that at a minimum studies should report on sample -size estimation , whether and how animals were r and omized , whether investigators were blind to the treatment , and the h and ling of data . We recognize that achieving a meaningful improvement in the quality of reporting will require a concerted effort by investigators , review ers , funding agencies and journal editors . Requiring better reporting of animal studies will raise awareness of the importance of rigorous study design to accelerate scientific progress 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 BACKGROUND Mutations in SOD1 cause 13 % of familial amyotrophic lateral sclerosis . In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis , the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival . We aim ed to assess the safety , tolerability , and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis . METHODS In this r and omised , placebo-controlled , phase 1 trial , we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses ( 0·15 mg , 0·50 mg , 1·50 mg , 3·00 mg ) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis ( six patients assigned to ISIS 333611 , two to placebo in each cohort ) . We did the r and omisation with a web-based system , assigning patients in blocks of four . Patients and investigators were masked to treatment assignment . Participants were allowed to re-enrol in subsequent cohorts . Our primary objective was to assess the safety and tolerability of ISIS 333611 . Assessment s were done during infusion and over 28 days after infusion . This study was registered with Clinical trials.gov , number NCT01041222 . FINDINGS Seven of eight ( 88 % ) patients in the placebo group versus 20 of 24 ( 83 % ) in the ISIS 333611 group had adverse events . The most common events were post-lumbar puncture syndrome ( 3/8 [ 38 % ] vs 8/24 [ 33 % ] ) , back pain ( 4/8 [ 50 % ] vs 4/24 [ 17 % ] ) , and nausea ( 0/8 [ 0 % ] vs 3/24 [ 13 % ] ) . We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611 . No serious adverse events occurred in patients given ISIS 333611 . Re-enrolment and re-treatment were also well tolerated . INTERPRETATION This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide . ISIS 333611 was well tolerated when administered as an intrathecal infusion . Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders . FUNDING The ALS Association , Muscular Dystrophy Association , Isis Pharmaceuticals 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 atrophy . FUNDING Ionis Pharmaceuticals , Inc and Biogen In September 2016,theUSFood and DrugAdministration ( FDA ) approved eteplirsen ( Exondys 51 ) , a new drug for Duchenne muscular dystrophy ( DMD ) , overruling the recommendations of both its scientific staff and its external advisory committee . Duchenne muscular dystrophy is a progressive X-linked genetic disease caused by mutations in a gene that produces the protein dystrophin that helps stabilize muscle fibers . It is usually fatal by the third decade of life . No disease-modifying treatments are available . Eteplirsen offered a promising new therapeutic approach that would correct a mutation in a gene coding for dystrophin , allowing production of a truncated but functional version of the protein . In particular , eteplirsen was design ed to skip 
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We found that even though the use of delivery systems provides an advantage over naked AONs , it is not yet possible to select the most promising strategies .