The concentration of chitotriosidase 1 (CHIT1) increases during treatment with the antisense oligonucleotide nusinersen (Spinraza®) in patients with spinal muscular atrophy (SMA), a new study published in the Orphanet Journal of Rare Diseases reported. This could indicate an immune response-like, off-target reaction to the treatment, according to the study authors.

“Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated,” Maren Freigang and Petra Steinacker, PhD, and co-authors concluded. However, levels of CHIT1 were also elevated in untreated patients with SMA, indicating the involvement of neuroinflammation in the disease.

“To the best of our knowledge, this is the first study showing elevated CHIT1 concentrations in SMA patients.” the researchers stated. However, they add that CHIT1 cannot be used as a marker of disease progression because there seems to be no correlation between its levels and the severity of the disease.

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Not much is known about the effect of repetitive intrathecal administration of antisense oligonucleotides in SMA on neuroinflammation and inflammatory response. However, cases of hydrocephalus, which can be the result of the inflammation of brain tissue, although rare, have been reported during nusinersen treatment in SMA patients.

Researchers assessed CHIT1 concentrations in 58 adults and 21 children with SMA type 1, 2, or 3 before the start of nusinersen treatment and compared them to controls. They also investigated the dynamics of CHIT1 concentration during treatment. At the same time, the researchers assessed the patients’ motor performance and disease severity.

The research team found that the levels of CHIT1 were higher in untreated SMA patients compared to controls but not as high as in diseases such as ALS. They also found that there was no correlation between levels of CHIT1 and the severity or the type of SMA.  

However, there was a significant increase in the concentration of CHIT1 during nusinersen treatment. This increase did not correlate with the clinical response to therapy.

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“Whether this observation is limited to nusinersen or represents a general reaction to intrathecal [antisense oligonucleotide] administration, needs to be further evaluated, since it is an establishing approach in the treatment of neurodegenerative diseases,” the authors concluded.

CHIT1 is an enzyme expressed by polymorphonuclear neutrophils and activated macrophages, which is thought to be involved in innate immunity. Its levels are elevated in many diseases including Gaucher disease, Alzheimer’s disease, MS, and ALS. 


Freigang M, Steinacker P, Wurster CD, et al. Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy. Orphanet J Rare Dis. 2021;16;330. doi:10.1186/s13023-021-01961-8