Spinal muscular atrophy (SMA) therapies
Drugs that raise the SMN protein that motor neurons lack in SMA: by changing SMN2 splicing or by adding a working SMN1 gene.
What they are
Spinal muscular atrophy is caused by loss of both copies of the SMN1 gene; the nearly identical SMN2 gene makes only a little full-length SMN protein, and its copy number modifies severity. Nusinersen (intrathecal antisense oligonucleotide) and risdiplam (oral small molecule) make SMN2 produce more full-length protein; onasemnogene abeparvovec is a one-time gene therapy that delivers a functional SMN gene.
Mechanism of action
Most SMN2 transcripts skip exon 7, giving a short, unstable protein. Splicing modifiers shift SMN2 splicing towards exon 7 inclusion, so more functional SMN is made. Gene therapy instead uses an adeno-associated virus vector to deliver a full copy of the human SMN gene into motor neurons. In both cases more SMN protein keeps motor neurons alive.
Target: SMN protein supply: SMN2 pre-mRNA splicing, or SMN1 gene replacement
Drugs in this class
- NusinersenAntisense oligonucleotide injected by lumbar puncture for spinal muscular atrophy. It makes SMN2 produce more…SMN2 pre-mRNA (intronic splicing silencer ISS-N1 in intron 7)
- RisdiplamFirst oral drug for spinal muscular atrophy: a small molecule that modifies SMN2 splicing to raise full-length SMN…SMN2 pre-mRNA splicing
- Onasemnogene abeparvovecOne-time intravenous gene therapy for spinal muscular atrophy in children under two. An AAV vector delivers a working…Survival motor neuron (SMN) protein, by replacement of the SMN1 gene
Test yourself
Think of the answer, then tap the question to see it.
Which gene is lost in spinal muscular atrophy, and which gene modifies severity?
SMN1 is lost on both copies; the SMN2 copy number modifies severity.
What do nusinersen and risdiplam have in common?
Both change SMN2 splicing so that exon 7 is included and more full-length SMN protein is made.
How does onasemnogene abeparvovec differ from the splicing modifiers?
It is a one-time AAV gene therapy that delivers a functional SMN gene instead of modifying SMN2.
Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: Spinal muscular atrophy: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2018); Nusinersen as a Therapeutic Agent for Spinal Muscular Atrophy (Yonsei Medical Journal, via PubMed Central, 2020); FDA approves innovative gene therapy to treat pediatric patients with spinal muscular atrophy, a rare disease and leading genetic cause of infant mortality (U.S. Food and Drug Administration, 2019); FDA Approves Oral Treatment for Spinal Muscular Atrophy (U.S. Food and Drug Administration, 2020).
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Representative model, for educational purposes only.