Antisense Oligonucleotides (ASOs) (modulation of the SMN2 'back-up' gene)
Modulation of the SMN2 ‘Back-up’ Gene
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, and 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. A number of treatment strategies that target SMN2 to make more functional SMN protein are being explored; they aim to do this in one of three main ways:
- Correct SMN2 splicing, allowing SMN2 to more efficiently produce functional SMN protein:
- Increase the protein production from SMN2 leading to more functional SMN protein.
- Stabilise the functional SMN protein made by SMN2 and therefore make it last longer.
Antisense oligonucleotide drugs are small snippets of synthetic genetic material that bind 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. They do this by binding to the RNA template made by SMN2 and enhancing the inclusion of exon 7 into the SMN protein. (See the above link for a more detailed explanation).
For an up to date view of progress see:
ASOs were used in mice to show that it is likely that SMN protein levels will need to be restored throughout the body, and not just the nervous system, in order to have the best chances of successfully treating the disease in patients.
NOVEL ANTISENSE THERAPY REMOVES THE BRAKES ON SMN PROTEIN PRODUCTION