SMA treatment normalizes blood signals linked to inflammation

Treating adults with late-onset spinal muscular atrophy (SMA) with Evrysdi (risdiplam) partially normalized changes in certain RNA molecules found in blood, a study found.

These molecules — cell-free messenger RNA (ccfmRNA) — are associated with inflammation and cellular stress. They are found in various bodily fluids, including blood, and may serve as biomarkers of neurological diseases. They may stem from cellular stress and degeneration, and may reflect disease-related processes.

Blood “ccfmRNA profiling may provide a useful exploratory framework for studying disease-related processes and treatment-associated changes in adult [late-onset SMA],” the researchers wrote.

However, the study found that ccfmRNA associated with glial cells, which support neurons, and blood vessel function remained altered during treatment.

The study, “Serum circulating cell-free messenger RNA profile response to risdiplam treatment in adult patients with late-onset spinal muscular atrophy,” was published in Brain Communications.

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Gene mutations lead to muscle weakness

SMA is caused by mutations in the SMN1 gene, resulting in a shortage of the survival motor neuron (SMN) protein and the loss of motor neurons, the nerve cells that control muscle movement. This leads to progressive muscle weakness and wasting.

Evrysdi is an oral disease-modifying treatment that works by increasing the amount of working SMN protein produced from a backup gene known as SMN2.

While SMN-enhancing treatments have improved outcomes in SMA, adults with late-onset disease may experience more limited functional gains because substantial motor neuron loss may have already occurred before they began treatment. Researchers are looking for biomarkers that could help monitor disease-related biological changes and treatment response.

Here, researchers in Germany analyzed blood samples from 23 adults with late-onset SMA (mean age 36, 60.9% men) — 15 with type 2 and eight with type 3 disease — and 12 healthy controls.

Blood samples from 17 participants were collected before starting Evrysdi and again after eight to 12 months and 12–14 months of treatment.

At baseline (study start), the researchers identified 17 ccfmRNA whose levels differed significantly between adults with SMA and healthy controls. Fourteen were elevated, including CCL3, CCL5, TLR2, and SQSTM1, which are associated with immune activity, inflammation, and cellular stress. Three others were reduced, including S100B and BCAS1, which are related to glial cells (non-neuronal cells of the nervous system).

Evrysdi treatment normalized levels of several immune- and stress-related ccfmRNA molecules. However, ccfmRNAs associated with glial and blood vessel function remained altered. “The differential behaviour of these markers compared with inflammatory genes suggests that [Evrysdi] preferentially normalizes immune activation rather than glial or [blood vessel] signalling,” the researchers wrote.

They also found more pronounced molecular abnormalities in people with type 2 SMA than in those with type 3. However, the scientists noted that these results require confirmation in larger studies, given the small number of participants with type 3 SMA.

An exploratory analysis also examined seven patients who switched from Spinraza (nusinersen), an injectable treatment that also increases SMN protein production, to Evrysdi.

Following the switch, the researchers observed additional changes in ccfmRNAs associated with epigenetic regulation (mechanisms that regulated gene activity without altering the underlying DNA sequence), fat metabolism, and neuronal function.

“Although these observations are based on a small subset of seven individuals and must be interpreted with great caution, they support the emerging view that the sequencing and combination of SMN-enhancing therapies may be biologically meaningful and that molecular monitoring could help to optimize clinical decision-making,” the investigators wrote.

They suggested that the changes seen after the switch may reflect the different ways through which the two drugs work and their different routes of administration.

The researchers also emphasized that the analysis did not account for potential influences such as physical activity, kidney function, and age, which could affect circulating RNA.

“The present results are preliminary and require validation in larger prospective cohorts before conclusions regarding the subtype classification, treatment switching, response prediction, or clinical decision-making can be drawn,” the team concluded.