The histone deacetylase inhibitor valproic acid cooperates with nusinersen-like antisense oligonucleotides to promote the inclusion of exon 7 and transcriptional elongation from the SMN2 gene, which means that more functional SMN protein can be made from the SMN2 gene. This approach could increase the efficacy of nusinersen and other antisense oligonucleotides for the treatment of spinal muscular atrophy (SMA).

In a study published in Cell, a team of researchers led by Alberto R. Kornblihtt, PhD, from the University of Buenos Aires in Argentina used a mouse model with SMA to combine nusinersen-like antisense oligonucleotide and valproic acid. It demonstrated not only synergized SMN expression but also improved growth, survival, and neuromuscular function.

“Our results pave the way toward clinical assessments in patients,” they wrote. 

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Nusinersen-like antisense oligonucleotides work by displacing splicing repressors from their target site in intron 7. However, they also promote the deployment of a silencing histone mark on the SMN2 gene. This creates a roadblock for RNA polymerase 2 elongation and inhibits the inclusion of exon 7 in the SMN2 mRNA.

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Valproic acid, which is already approved for clinical use, removes the roadblock. This way, it counteracts the chromatin effects of the antisense oligonucleotides. The result is a higher inclusion of exon 7 in the SMN2 mRNA without large pleiotropic effects.

SMA is caused by a mutation in the SMN1 gene, which is the gene from which most of the SMN protein is made. The mutation means that only a little SMN is made. SMN is essential for the survival of motor neurons, so in its deficiency, motor neurons die leading to the symptoms of SMA. It is thought that the number of copies of the SMN2 gene, which varies among individuals is inversely correlated with the severity of the disease.


Marasco LE, Dujardin G, Sousa-Luís R, et al. Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy. Cell. 2022;185(12):2057-2070.e15. doi:10.1016/j.cell.2022.04.031