Researchers proposed a novel mechanism by which inhibitors of the sodium-protein exchanger (NHE5) increase the inclusion of exon 7 in the SMN2 gene and published their results in Molecular Pharmacology. This suggests that NHE5 inhibition could be a new therapeutic avenue for spinal muscular atrophy (SMA).
Previous work has shown that the NHE inhibitor 5-(N-ethyl-N-isopropyl)amiloride (EIPA) increases exon 7 inclusion in SMN2 and SMN protein levels in a mouse model of SMA.
Here, a team of researchers led by Matthew E. R. Butchbach, PhD, from the Department of Neurology, Nemours Children’s Hospital in Delaware evaluated NHE inhibitors for their ability to modulate the expression of the SMN2 gene.
They found that EIPA and 5-(N,N-hexamethylene)amiloride (HMA) increase the inclusion of exon 7 in the SMN2 gene. Moreover, they showed that EIPA induced the inclusion of exon 7 through a mechanism not involving known splicing factors but rather by targeting the expression of novel genes such as TIA1 and FABP3.
“This study provides a novel means to increase full-length SMN2 expression and a novel target for therapeutics development,” the researchers said.
Read more about SMA experimental therapies
SMA is caused by a mutation in the SMN1 gene, which is the primary gene from which SMN is made, a protein essential for the the survival of motor neurons. In the absence of SMN production from SMN1, the body relies of SMN produced from a second very similar gene called SMN2.
However, most of the SMN protein produced from this gene is nonfunctional due to alternative splicing that leaves exon 7 out of the transcript. SMN2 exon 7 inclusion approaches have been the focus of therapeutic research for many years.
The TIA1 gene codes a protein that binds to the RNA and regulates alternative splicing. FABP3 codes for a member of fatty acid-binding proteins, which is highly expressed in the heart and skeletal muscles. Although the exact role of FABP3 is not known, it is considered to be a lipid chaperone that regulates the solubility, mobility, and utilization of fatty acids.
Kanda S, Moulton E, Butchbach MER. Effects of inhibitors of SLC9A-type sodium-protein exchangers on survival motor neuron2 (SMN2) mRNA splicing and expression. Mol Pharmacol. Published online June 6, 2022. doi:10.1124/molpharm.122.000529