Certain CSF Biomarker May Foretell Nusinersen Response in Children With SMA

A certain biomarker in cerebrospinal fluid (CSF) may be helpful for predicting response to treatment among pediatric patients with spinal muscular atrophy (SMA), found a recent study published in Brain & Development.

Using data from a group of patients with SMA type 1 and 2, researchers observed that chitotriosidase 1 (CHIT1) levels in CSF changed throughout treatment with nusinersen, suggesting that the change could be indicative of treatment response.

“CHIT1 is a human endochitinase expressed by polymorphonuclear neutrophils and activated macrophages that is thought to be involved in innate immune system responses. CHIT1 is upregulated in neurological conditions like acute ischemic stroke, Alzheimer disease, and multiple sclerosis,” explained the researchers, noting that their study is the first to show utility of CHIT1 in pediatric SMA.

Six patients were enrolled in the study, all of whom were treated with nusinersen between 2018 and 2021. Although CHIT1 levels in CSF trended toward significant increases during the first year of treatment, the levels significantly decreased between the first and second years of treatment (mean change, –407.8 pg/mL; P = .031]. Meanwhile, CSF inflammatory cytokines TNF-α and INF-γ remained unchanged over the time period.

CHIT1 levels in the 2 patients with SMA type 1 dropped from 2845.6 to 2112.0 pg/mL and from 957.6 to 453.3 pg/mL. Among the 4 patients with SMA type 2, levels dropped from 532.4 to 310.6, 1260.0 to 682.4, 485.0 to 297.3, and 648.0 to 424.2 pg/mL.

According to the researchers, their findings differ from previous results published by Freigang et al, which characterized CHIT1 levels between baseline and 14 months, compared with changes between 1 to 2 years assessed in the current study, accounting for long-term treatment. The previous findings also came from a different patient population, with data being pulled mainly from adults.

“The difference in results between our study and Freigang et al likely reflects the difference in study populations and the length of treatment,” detailed the present study investigators. “We do not know why the CHIT1 level increased in our cohort during the first year of treatment, but neuroinflammatory processes, including off-target effects, might affect CHIT1 levels before the effects of treatment are felt. In patients with early-stage SMA, nusinersen may eventually reduce such neuroinflammatory processes and improve motor function.”

These decreases in CHIT1 levels observed between the first and second year of treatment in the current study correlated with improvements in motor function. During the time period, there was a trend toward an inverse correlation between motor function scores and CHIT1 levels, although the researchers noted there was no statistical significance. According to the group, this may resulted from the small number of patients in their study, which made it difficult to make a correlation between CHIT1 and severity of disease.

The group also noted the lack of a control group included in their study, leading them to refer to previously published data on normal CHIT1 levels in CSF and creating a need for a larger multicenter study.

Reference

Kobayashi Y, Ishikawa N, Tateishi Y, et al. Evaluation of cerebrospinal fluid biomarkers in pediatric patients with spinal muscular atrophy. Brain Dev. Published online October 6, 2022. doi:10.1016/j.braindev.2022.09.008