Nusinersen: the antisense oligonucleotide at the forefront of spinal muscular atrophy treatment
Year: 2026
Type: article
Abstract: Spinal muscular atrophy (SMA) is the first human disease to be treated with an antisense oligonucleotide (ASO) that restores the full coding sequence of a mRNA through splicing modulation. The therapeutic ASO nusinersen (marketed as SpinrazaTM) targets intronic splicing silencer N1 (ISS-N1) located downstream of the predominantly skipped exon 7 of Survival Motor Neuron 2 (SMN2) gene. The full-length transcript of SMN2 codes for SMN, an essential housekeeping protein with a prominent role in RNA metabolism. The success of nusinersen could be attributed at least in part to the accessibility of ISS-N1 that was found to have a strong inhibitory effect on splicing of SMN2 exon 7. Nusinersen has saved thousands of lives affected by SMA. However, limitations of an ASO-based therapy continue to emerge. Here we describe lessons learned from ASO-mediated splicing corrections in general and nusinersen in particular. Specific focus of this review is to discuss how information gleaned from the off-target effects of nusinersen could be utilized to develop next generation of ASO-based therapies with improved efficacies.
Source: RNA Biology
Institution: Iowa State University
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,175
OpenAlex ID: W7161547082