SMA research offers clues into how splice-modifying therapies work

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by Lindsey Shapiro PhD |

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A graphic showing a scissor cutting or splicing a double-helix strand of DNA.

New research has identified mechanisms by which Evrysdi (risdiplam), an approved spinal muscular atrophy (SMA) therapy, has more specific effects at its target gene than branaplam, a similar molecule that was investigated as a possible SMA treatment, but later discontinued.

Both molecules modify a process called splicing in the SMN2 gene. Combining multiple splice-modifying molecules, including Evrysdi with branaplam, appeared to have synergistic effects that could make them more effective.

“Our new study provides insights into the action and specificity of splice-modifying drugs,” Adrian Krainer, PhD, professor at Cold Spring Harbor Laboratory (CSHL) in New York and a study author, said in a press release. “This should facilitate the development of more effective drugs and drug combinations for a variety of diseases.” The study, “Specificity, synergy, and mechanisms of splice-modifying drugs,” was published in Nature Communications.

SMA is caused by mutations in the SMN1 gene, leading to a lack of the SMN protein. SMN2 is a backup SMN-producing gene, but it produces only about 10%-15% of the protein due to a cellular event called alternative splicing, essentially, the natural process by which a single gene gives rise to multiple versions of a protein.

When DNA is being read to make a protein, it’s first transcribed into a template molecule called messenger RNA (mRNA). For mature mRNA to be made, portions of the genetic code called introns are cut out and the remaining protein-coding segments (exons) are strung back together. When these cuts are made in different ways and the remaining exons are strung back together in different combinations, multiple mRNA templates are created, and thus, multiple protein products. In SMN2, such a splicing event causes exon 7 to be excluded from mRNA, leading to a shorter and less stable SMN protein being produced.

Approved SMA therapies Spinraza and Evrysdi are SMN2 splice-modifying therapies that alter splicing to prevent exon 7 exclusion and allow more functional SMN protein to be produced. Spinraza is an antisense oligonucleotide (ASO), a small strand of genetic material, that’s designed to promote exon 7 inclusion.

It’s not fully understood how Evrysdi, an oral small molecule, targets SMN2. That’s also the case with branaplam, a molecule with a similar mechanism that was being developed for SMA, but was discontinued in 2021. Branaplam is less specific for SMN2 than Evrysdi is.

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Targeting SMN2 splicing

Here, researchers sought to learn more about how the two molecules target SMN2 splicing. Both bind to what’s known as splice sites on SMN2, sequences on the code that tell the cellular machinery where to make cuts during splicing.

While Evrysdi seems to have one interaction mode at these sites, branaplam has two distinct modes, one that’s similar to how Evrysdi acts and one that’s different. The distinction could explain why branaplam is less specific for SMN2’s exon 7 than Evrysdi is.

Previous research suggested Evrysdi might promote exon 7 inclusion by binding to these splice sites and to another section of the SMN2 code called a purine tract. This study showed the so-called two-site hypothesis doesn’t hold up; Evrysdi doesn’t bind to that purine tract.

Combinations of different splice-modifying molecules, including Evrysdi, branaplam, and various ASOs that target the same exon, but in different ways, had a greater effect on SMN2 splicing than a single molecule alone.

“You get synergistic interactions,” CSHL associate professor Justin Kinney said. “This might provide a basis for using drug cocktails instead of individual drugs.”

That’s consistent with other recent findings, wherein combinations of Evrysdi with branaplam or Spinraza had more benefits than Evrysdi alone.

The findings “reveal details about the mechanisms of two clinically important drugs, and suggest new approaches for developing therapeutics,” wrote the researchers, who said the quantitative modeling approach used to answer these questions about Evrysdi and branaplam can be applied to learn more about splice-modifying treatment candidates for a variety of diseases.

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