Evrysdi and Spinraza Target SMN2 Gene, But in Different Ways
While humans have a “backup” SMN gene, called SMN2, a slight difference in its DNA sequence results in an event called “alternative splicing” that limits the amount of functional SMN it produces to 10–15%.
Alternative splicing allows for a single gene to give rise to many different proteins. Much like in a recipe, adding or removing certain key ingredients — in this case, pieces of genetic information called exons — can change the results: the messenger RNA (mRNA) and the final protein. (mRNA is a molecule derived from DNA and used as a template for protein production.)
Splicing of an exon depends on the balance between splicing enhancers — DNA sequences that recruit proteins to stimulate exon inclusion — and splicing silencers, those that recruit splicing suppressor proteins to prevent exon inclusion in the final mRNA.
The slight change in SMN2’s sequence causes an unbalance between exon 7 splicing enhancers and silencers, leading this exon to be excluded from most of the SMN2 mRNA molecules. The result is a shorter, poorly functioning SMN protein.
Spinraza and Evrysdi both work to correct SMN2’s alternative splicing, preventing exon 7 deletion from mRNA and “restoring” the production of a functional SMN protein.
But they do it in different ways.
Spinraza works by binding to exon 7’s main splicing silencer, blocking its interaction with a splicing suppressor called hnRNP A1. Evrysdi is thought to interact with distinct splicing sites, working in concert with the splicing regulatory network to stabilize a splicing enhancer called ESE2. (ESE stands for exonic splicing enhancer.)
Spinraza belongs to a group of molecules called antisense oligonucleotides (ASOs). These synthetic single-stranded RNA molecules are designed to be complementary to the target premature mRNA, altering the mature mRNA and the resulting protein.
Since ASOs are large negatively charged molecules, they do not efficiently cross the blood-brain barrier. This barrier is a specialized membrane that prevents molecules larger than 400–500 Dalton (a measure of molecular weight) and potentially harmful microorganisms like bacteria, which circulate in the blood, from reaching the brain.
Evrysdi is a small molecule, optimized to be safe and as specific as possible. As a small molecule, it can pass the blood-brain barrier, allowing it to be taken orally and to distribute across the brain and to peripheral tissues.
Both treatments, clinical trials have shown and experts interviewed for this series affirm, are safe and effective for patients.