A Promising New Drug Combo Could Improve Spinal Muscular Atrophy Treatment

The study found that pairing Spinraza® with valproic acid could boost its effects.

A New Drug Duo

Spinraza® changed the game for people with spinal muscular atrophy (SMA) in 2016. It was the first medication for the neurodegenerative condition that is the leading genetic cause of infant mortality to get FDA approval. Cold Spring Harbor Laboratory (CSHL) Professor Adrian Krainer and colleagues conceptualized and developed the medication.

Krainer didn’t stop there, however. Together with Alberto Kornblihtt at the Universidad de Buenos Aires, his lab has been looking into whether Spinraza® could be enhanced. They identified a novel strategy to enhance the therapeutic benefits of Spinraza® by combining it with valproic acid (VPA), a separate FDA-approved drug.

Increasing a drug’s dose is one method for increasing its impact. But like with any drug, using more Spinraza® puts you at risk for negative side effects. Krainer and his associates used a different strategy. They found that combining Spinraza® with VPA could be an alternative method for increasing its clinical effect without using more of the drug. Krainer explains:

“Sometimes you don’t want to use a ton of a drug. If you have a condition that allows you to use less of the 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. Krainer’s latest research shows that there’s always room for improvement. He hopes the team’s findings will help optimize the efficacy of Spinraza® treatments. He also hopes their work will help researchers who are trying to develop therapies for other neurodegenerative diseases.

Reference: “Counteracting chromatin effects of a splicing-correcting antisense oligonucleotide improves its therapeutic efficacy in spinal muscular atrophy” by Luciano E. Marasco, Gwendal Dujardin, Rui Sousa-Luís, Ying Hsiu Liu, Jose N. Stigliano, Tomoki Nomakuchi, Nick J. Proudfoot, Adrian R. Krainer and Alberto R. Kornblihtt, 9 June 2022, Cell.
DOI: 10.1016/j.cell.2022.04.031

The study was funded by Familias Atrofia Muscular Espinal, CureSMA, Richard Lounsbery Foundation, Universidad de Buenos Aires, Agencia Nacional de Promoción Científica y Tecnológica of Argentina, NIH/National Institutes of Health, Consejo Nacional de Investigaciones Científicas y Técnicas, St. Giles Foundation, Fundação para Ciência e a Tecnologia.

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