Spinraza Linked to Temporary Abnormalities in Immune Cells in 2 SMA Infants

Repeated administrations of Spinraza (nusinersen) were associated with the presence of macrophages — immune cells specialized in recognizing and eliminating harmful organisms and dead cells — with unusual features in the spinal fluid of two infants with spinal muscular atrophy (SMA), a case study reports.

While these abnormalities alone could suggest the presence of fungal infections or lysosomal storage disorders, their temporary nature and the absence of other relevant symptoms point to Spinraza as the potential cause, the researchers noted.

The case report, “Unusual inclusions in cerebrospinal fluid macrophages of spinal muscular atrophy patients treated with nusinersen,” was published as a letter to the editor in the International Journal of Laboratory Hematology.

Reported by researchers at Massachusetts General Hospital, these findings add to a similar previous report in adults with SMA, highlighting the need for physicians to be aware of these transitory, abnormal features in patients receiving Spinraza to avoid excessive concern and misdiagnosis.

Still, further studies are needed to determine the significance and composition of these unusual vesicles.

Spinraza, an antisense oligonucleotide (ASO) developed by Biogen, was the first disease-modifying therapy approved for all types of SMA. It works to increase the production of a functional survival motor neuron protein, which is essential for motor neuron and muscle health and lacking in people with SMA.

Spinraza is injected directly into the cerebrospinal fluid (CSF; the fluid that surrounds the brain and spinal cord), through spinal taps, at a recommended regimen of four 12 mg doses in the first two months, followed by maintenance treatment at the same dose every four months.

Its safety and effectiveness were well-established in clinical trials before its approval, and has been further confirmed through an increasing number of real-life studies. While safety assessments in these trials included measures of several important parameters in patients’ CSF, they did not do profound analyses of cells in the CSF.

The previous study evaluated cellular changes in CSF over time in 19 adults treated with Spinraza in Germany. Results showed that the therapy did not result in long-term inflammatory cellular changes or relevant shifts in white blood cell subsets.

However, the researchers found macrophages with numerous abnormal, round intracellular vesicles in the CSF of all patients at least at one time point. Emerging after the second Spinraza dose, these cells appeared to fade with time in most patients.

Notably, these unique macrophages were not observed in the CSF of people who had undergone repeated spinal taps due to other diseases.

In the current case report, the first patient was a 24-day-old boy diagnosed with type 1 disease receiving his second dose of Spinraza. His CSF, collected prior to the second dose, showed abnormally high counts of macrophages (when they are usually absent in the CSF) with numerous unusual intracellular vesicles.

Notably, these unique macrophages were still present in the infant’s CSF prior to the third dose, but absent before the fourth dose, which was given two months after the second dose.

Similar macrophage counts with the same unusual vesicles were observed in the CSF of a 36-day-old boy, whose diagnosis was likely type 3 or 4 (adult-onset) disease, before his third Spinraza dose. No abnormalities were noted one month later before the fourth dose was given.

The proportion of other immune cells in the CSF were within normal ranges in both patients.

The team noted that these abnormal findings initially raised concern over a fungal infection or the presence of a lysosomal storage disorder, both of which can lead to similar vesicles in immune cells.

However, the boys’ “reassuring physical findings,” including no fever, seizures, or lack of energy, and absence of significant findings in other immune cells “rendered such serious diagnoses unlikely,” the researchers wrote, adding that Spinraza administration was “the most likely culprit.”

These and previous findings suggest that Spinraza is associated with a likely temporary and harmless appearance of macrophages with unusual vesicles, but the nature and significance of these vesicles remain unclear.

While it is possible that these vesicles contain ASO particles, other studies suggest they may contain immune-signaling molecules due to macrophage activation, the team noted. Future studies are needed to clarify this.

“Regardless of the nature of the [vesicles], knowledge of their occurrence in SMA and potentially other diseases treated by [ASOs given directly into the CSF] is important in correctly identifying this striking finding and avoiding misdiagnosis of infection,” the researchers wrote.