In 2016, Spinraza® became a game-changer for spinal muscular atrophy (SMA) patients. It was the first FDA-approved treatment for the neurodegenerative disease, which is the leading genetic cause of infant death.

One way to improve the effect of a drug is by increasing its dosage. But as with any drug, increasing the amount of Spinraza® also increases the risk of toxic side effects. The authors took a different approach. They discovered that pairing Spinraza® with valproic acid (VPA) may be an alternate way to improve its clinical effect without using more of the drug.

The senior author explains: “Sometimes you don’t want to use a ton of a drug. If you have a condition that allows you to use less drug, then you may have fewer toxicities. So the idea is to combine these two drugs to get maximal effects.”

People with SMA don’t have enough of a protein called SMN. Spinraza® is a type of molecule called an antisense oligonucleotide (ASO) that helps cells make more SMN protein from a gene called SMN2. The team discovered that there were roadblocks on the SMN2 gene when using Spinraza®. This slowed down the cellular machine producing SMN protein. The drug VPA helps remove the roadblocks, allowing Spinraza® to further increase the SMN protein output.

When mice with SMA were treated with both VPA and a Spinraza®-like ASO used for research, the mice survived longer and had improved muscle function.

Over 11,000 SMA patients have been treated with Spinraza® in more than 50 countries.

https://www.cell.com/cell/fulltext/S0092-8674(22)00529-3