Research in context
Evidence before this study
Spinal muscular atrophy is caused by deletions or mutations in the Survival Motor Neuron 1 (SMN1) gene and is the most common genetic cause of childhood mortality. Infantile-onset spinal muscular atrophy presents clinically as a severe, progressive motor neuron disease, resulting in generalised weakness and impaired feeding and breathing. Survival is dependent upon a small amount of normal SMN protein translated by the backup SMN2 gene, which, due to a splice site variant, usually excludes exon 7. Less than a quarter of these infants survive beyond 2 years of age without dependence upon ventilation support. There are no approved drug treatments for spinal muscular atrophy. Antisense oligonucleotides provide a targeted strategy for spinal muscular atrophy treatment by specifically binding to repressive sites within SMN2 exon 7 or the flanking introns, thus promoting exon 7 inclusion and increased production of functional SMN protein. Nusinersen (also known as ISIS 396443 and ISIS-SMNRx) is a uniformly modified 2'-O-methoxyethyl phosphorothioate antisense oligonucleotide being developed for the treatment of spinal muscular atrophy. We searched PubMed using the keywords “nusinersen”, “ISIS 396443”, “ISIS-SMNRx “, and “ASO 10-27” with no date restrictions. Of the six publications identified, two reported the results of the phase 1 study described below, three described preclinical results using nusinersen, and one was a review article on SMA therapeutics. A phase 1, short-term, single-dose clinical study of intrathecally delivered nusinersen was previously done in children with spinal muscular atrophy.
Added value of this study
We report interim results of an ongoing open-label, phase 2, multiple-dose study of intrathecal nusinersen in patients with severe infantile-onset spinal muscular atrophy. We provide evidence that nusinersen has acceptable safety and tolerability when delivered by multiple intrathecal injections and shows promising clinical efficacy as evidenced by improvements in motor function, achievement of motor milestones, and permanent ventilation-free survival as compared with published natural history. Additionally, autopsies collected during the study indicate proof of target engagement and mechanism, as nusinersen altered SMN2 splicing, with an increase in full-length transcript that includes exon 7, and an increase in SMN protein in spinal cord motor neurons as compared with untreated infants with spinal muscular atrophy as control.
Implications of all the available evidence
Our study shows favourable safety and tolerability, pharmacokinetics, proof-of-concept pharmacodynamics, and a promising clinical response of intrathecal nusinersen. Results informed the design of an ongoing large phase 3, randomised, sham-controlled study of nusinersen in infantile-onset spinal muscular atrophy. More broadly, the mechanistic effects of nusinersen at the mRNA and protein level in participants of this study provides proof of principle for the use of antisense therapeutics in the treatment of neurological disorders. Finally, results from this study suggest treatments that increased SMN protein might provide clinical benefit to patients with spinal muscular atrophy.