Children with later-onset spinal muscular atrophy benefited from three years of treatment with the anti-sense oligonucleotide nusinersen, according to a paper in today’s Neurology. Motor function either improved or stabilized in kids aged 2 to 15 who had SMA Type 2 or 3. The results confirm previous studies suggesting the drug halts or reverses disease progression, and broadens both the age range and treatment period for efficacy.

  • Twenty-eight children with SMA Type 2 or 3 were injected with the ASO nusinersen four times in two years.
  • Motor function and walking distance improved.
  • Results hint that nusinersen can halt or reverse SMA progression.

In a Neurology editorial, Emma Ciafaloni, University of Rochester, New York, and Barry Russman, Oregon Health & Science University School of Medicine, Portland, note that the SMA community had long awaited these results.

“The degree of change in three different motor scales and the gain or regain of ambulation reported here are outside of what is expected in the natural history of patients with SMA Type 2 or 3,” they wrote.

Twenty-eight patients enrolled in this open-label extension. It followed a 253-day Phase 1b/2a trial in SMA Type 2 or 3, which have onset ages of 7 to 18 months, or older, respectively. Children with Type 2 can usually sit unsupported, but some lose that ability as they get older. Most cannot stand. Children with Type 3 can walk independently, though again, some lose that as they get older.

In the extension, 12 mg of nusinersen was injected intrathecally into the cerebrospinal fluid once every six months for two years. The researchers evaluated motor function using the Hammersmith Functional Motor Scale–Expanded (HFMSE). For children who couldn’t walk, the Upper Limb Module (ULM) test measured arm function. In ambulatory kids, the 6-Minute Walk Test (6MWT) measured how far they could walk in that time. To determine the degree of nerve innervation of muscles, authors measured the compound muscle action potential (CMAP).

By the end of the trial, average scores on all motor tests had improved. For the 11 children with SMA Type 2, none of whom could walk independently at the beginning of the trial, the HFMSE score rose 10.8 points, and the ULM score by 4 points. One child could walk by the end of the trial, working up to 180 meters on the 6MWT. For the 17 children with SMA Type 3, the HFMSE score inched up a more modest 1.8 points, possibly because scores started higher in this group and children had to squat, jump, and climb stairs to demonstrate improvement. However, these children gained an average 92 meters in the 6MWT, three times longer than considered clinically meaningful. Two of the four children with SMA Type 3 who had lost the ability to walk before the trial were walking by the end. Average CMAP values stayed about the same.

There was no control group. Study first author Basil Darras of Boston Children’s Hospital and colleagues compared these results with an average 1.7-point decline on the HFMSE over three years in a natural history cohort of children with SMA Type 2 or 3 (Kaufmann et al., 2012). The mechanism of improvement is still unknown, but could have to do with axonal growth and function, re-innervation of muscle fibers, and maturation of synapses brought on by an increase in SMN production.

Other oligonucleotide-based therapies for neurodegenerative diseases are on the horizon. Hoffman-LaRoche has begun a Phase 3 trial of its ASO RG6042 that targets the huntingtin protein in patients with early Huntington’s disease (Mar 2018 news). Phase 1b/2a trials are underway by Wave Life Sciences for the ASOs WVE- 120101 and WVE-120102, which also target mutant huntingtin protein. Other ASOs are in pre-clinical studies or clinical trials for diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis, spinocerebellar ataxia, and familial amyloid polyneuropathy (May 2018 conference news; May 2018 conference news).—Gwyneth Dickey Zakaib


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News Citations

  1. Antisense Therapy Cuts Huntingtin Protein in CSF by Half
  2. As RNA Therapies Come of Age, Efficacy Remains Weak
  3. At AAN, Sights Set on Antisense Therapies for Diseases of the Brain

Paper Citations

  1. . Prospective cohort study of spinal muscular atrophy types 2 and 3. Neurology. 2012 Oct 30;79(18):1889-97. Epub 2012 Oct 17 PubMed.

External Citations

  1. Phase 3
  2. WVE- 120101
  3. WVE-120102

Further Reading


  1. . Gene suppression approaches to neurodegeneration. Alzheimers Res Ther. 2017 Oct 5;9(1):82. PubMed.
  2. . Intrathecal administration of nusinersen in adolescent and adult SMA type 2 and 3 patients. J Neurol. 2019 Jan;266(1):183-194. Epub 2018 Nov 20 PubMed.

Primary Papers

  1. . Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies. Neurology. 2019 Apr 24; PubMed.
  2. . Nusinersen for SMA: Not just for babies?. Neurology. 2019 Apr 24; PubMed.