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For our lower motor neurons to function and remain healthy, our cells need to produce the survival motor neuron (SMN) protein. The ability to do this is mainly controlled by the survival motor neuron 1 (SMN1) gene.

The SMN2 gene also contributes to the production of SMN protein, though it only makes approximately 10% of that produced by SMN1. For this reason, SMA is caused only by mutations in the SMN1 gene and not SMN2. This is also why SMN2 is often called the SMN ‘back-up’ gene.

Anyone who has SMA has at least one copy of the SMN2 gene. Individuals can have multiple copies of SMN2 and, in general, it seems that those with more copies have a less severe form of SMA.

Most of the SMN protein made by SMN2 (about 90%) is missing an important piece called exon 7. The remaining 10% of the protein produced by SMN2 includes exon 7 and is the same as that made by SMN1.

Antisense oligonucleotide drugs (ASOs) are small snippets of synthetic genetic material that bind to ribonucleic acid (RNA). They are often described as molecular patches because they can be specifically designed to target and affect how a particular gene is read. ASOs have great potential for SMA, because they can accurately target the SMN2 gene to essentially convert it into the SMN1 gene, i.e. they are small molecules “patching-up” SMN2 to act more like SMN1. So they can be used to fix splicing errors in genes such as SMN2. They do this by binding to the RNA template made by SMN2 and enhancing the inclusion of exon 7 into the SMN protein.

Nusinersen is an antisense oligonucleotide that targets SMN2, causing it to make more complete SMN protein.

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