The survival motor neuron (SMN) protein is essential for the health of motor neurons. This protein is produced by a gene called survival motor neuron 1 (SMN1). People with spinal muscular atrophy (SMA) have a mutation in the SMN1 gene, which prevents it from producing SMN protein.
Sometimes called the “back-up gene,” SMN2 also helps produce SMN protein, even though it can only make a small amount of stable SMN protein. Anyone can have multiple copies of the SMN2 gene, though generally, those with more copies have a less severe form of SMA.
Researchers are exploring a series of therapeutic approaches that target SMN2 to make more functional SMN protein in one of three ways:
- By correcting SMN2 splicing, allowing the gene to more efficiently produce functional SMN protein;
- By increasing protein production from SMN2, leading to more functional SMN protein;
- By stabilizing the functional SMN protein made by SMN2 so it lasts longer.
Currently, researchers are investigating three compounds for their potential benefits:
Licensed by Pfizer, RG3039 is an orally bioavailable, brain-penetrating small molecule that has been shown to inhibit the mRNA decapping enzyme, Dcps. RG3039 has been shown to extend survival, improve function and affect neuromuscular pathology in three SMA mouse models of varying disease severity.
RG7916 is a small molecule designed to shift pre-mRNA splicing toward the production of full-length SMN mRNA from the SMN2 gene.
Valproic acid or valproate (VPA) is a histone deacetylase inhibitor (HDACI) that has been used since the 1970s as an anti-epileptic drug. It has recently demonstrated increased expression of SMN, supporting the possibility of therapeutic benefit in SMA.
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