BACKGROUNDSpinal 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. METHODSWe 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. RESULTSIn 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. CONCLUSIONSAmong 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.)

Ultrasound has been used for visualizing peripheral nerve pathology. Our goal was to use ultrasound to quantitate the sizes of upper extremity nerves along their length in control subjects and patients with neuropathy. We measured median and ulnar nerve cross-sectional areas (NCSA) in the arms of 190 subjects, including 100 with neuropathies and 90 controls. We found that NCSAs in healthy child and adult controls were greater with increasing height, at proximal sites, and at sites of entrapment. Nerves were enlarged in all Charcot-Marie-Tooth 1A (CMT-1A) (11 of 11; 100%), most chronic inflammatory demyelinating polyneuropathy (CIDP) (31 of 36; 86%), half of Guillain-Barré syndrome (GBS) (8 of 17; 47%), but few axonal neuropathy (7 of 36, 19%) subjects. In GBS, nerve enlargement occurred early and with minimal electrodiagnostic abnormalities in some patients. We conclude that NCSA measured by ultrasound is a quantifiable marker of nerve features that should be corrected for patient characteristics and nerve site. NCSA is generally larger in demyelinating than it is in axonal polyneuropathies.

No abstract

No abstract

IMPORTANCEAn unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease.OBJECTIVE To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping. DESIGN, SETTING, AND PARTICIPANTSThis phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened.