New Evrysdi study uncovers genetic differences in SMA types
A study in adults with spinal muscular atrophy (SMA) found that Evrysdi (risdiplam) helps the body produce more functional SMN protein, and also revealed molecular differences between SMA types 2 and 3 that may affect how the disease progresses and responds to treatment.
The findings, which showed differences in how cells produce energy and recycle unwanted material, may be of “some relevance for future clinical and therapeutic strategies,” the researchers wrote.
The study, “Longitudinal Transcriptomic Analysis Reveals Systemic Effects of Risdiplam in Adults with Spinal Muscular Atrophy,” was published in Brain Sciences.
SMA is caused when mutations in the SMN1 gene result in non-functional or low levels of the SMN protein, which is needed to keep motor neurons (the nerve cells that control muscles) alive. Without functional SMN protein, motor neurons die, and muscles weaken.
Evrysdi, a disease-modifying treatment approved for SMA, works by increasing SMN protein production from a backup gene, SMN2. Normally, SMN2 produces only a small amount of working protein. Evrysdi corrects RNA splicing, a process whereby genetic instructions are cut and edited, so that SMN2 produces more full-length, functional protein.
RNA sequencing tracks changes over time
For their study, the researchers collected blood samples from 16 adults diagnosed with SMA, with a mean age of 37.6, before and after 12 months of Evrysdi. Eleven patients had SMA type 2 and five had type 3, based on age at symptom onset. Data after 12 months were available for seven patients. None of the patients stopped Evrysdi during this period, but one later stopped due to severe gastrointestinal side effects.
The scientists used RNA sequencing, which measures which genes are active, to track molecular changes over time. Evrysdi increased levels of full-length SMN2 transcripts, copies of the RNA containing genetic information to produce proteins.
“This was particularly interesting considering the oral route of administration,” the researchers wrote.
They also found increased activity in mitochondrial genes. Mitochondria are the cell’s energy producers, so lower activity may reflect changes in energy demand in treated patients. Some pseudogenes, which resemble genes but do not produce proteins, were also more active. At the same time, genes involved in autophagy (the cell’s recycling mechanism, in which unwanted material is broken down and reused) were less active.
Before treatment, there were clear genetic differences between SMA type 2 and type 3, particularly in genes linked to neurodegeneration and immune function.
Because the study included a small number of patients, “these findings should be interpreted with caution,” the researchers wrote. “However, they raise the possibility that alterations in cellular components and processes involved in RNA metabolism and protein [production] may help discriminate between SMA type [2] and type [3],” they said.
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