Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

Abstract

Background Studies regarding the impact of (neuro)inflammation and inflammatory response following repetitive, intrathecally administered antisense oligonucleotides (ASO) in 5q-associated spinal muscular atrophy (SMA) are sparse. Increased risk of hydrocephalus in untreated SMA patients and a marginal but significant increase of the serum/CSF albumin ratio (Qalb) with rare cases of communicating hydrocephalus during nusinersen treatment were reported, which confirms the unmet need of an inflammatory biomarker in SMA. The aim of this study was to investigate the (neuro)inflammatory marker chitotriosidase 1 (CHIT1) in SMA patients before and following the treatment with the ASO nusinersen. Methods In this prospective, multicenter observational study, we studied CSF CHIT1 concentrations in 58 adult and 21 pediatric patients with SMA type 1, 2 or 3 before treatment initiation in comparison to age- and sex-matched controls and investigated its dynamics during nusinersen treatment. Concurrently, motor performance and disease severity were assessed. Results CHIT1 concentrations were elevated in treatment-naïve SMA patients as compared to controls, but less pronounced than described for other neurodegenerative diseases such as amyotrophic lateral sclerosis. CHIT1 concentration did not correlate with disease severity and did not distinguish between clinical subtypes. CHIT1 concentration did show a significant increase during nusinersen treatment that was unrelated to the clinical response to nusinersen therapy. Conclusions CHIT1 elevation in treatment-naïve SMA patients indicates the involvement of (neuro)inflammation in SMA. The lacking correlation of CHIT1 concentration with disease severity argues against its use as a marker of disease progression. The observed CHIT1 increase during nusinersen treatment may indicate an immune response-like, off-target reaction. Since antisense oligonucleotides are an establishing approach in the treatment of neurodegenerative diseases, this observation needs to be further evaluated.

Biochemical and clinical biomarkers in adult SMA 3–4 patients treated with nusinersen for 22 months

“…30 The increase in CHIT1 is thus probably not related to a therapeutic effect but might be caused by the repeated intrathecal administrations of an ASO leading to a mild inflammatory response, as suggested by Freigang et al (and supported by increased total protein levels in multiple studies). 16,31,32 After completion of the study, we analyzed CSF samples of 11/16 patients at month 30 of the treatment period, and found that four patients showed increased protein levels of which three had the highest CHIT1 levels in the study. No patients showed a pleocytosis.…”

“…14,15 No such data are currently available for individuals with SMA, except for a single recent study that concluded that baseline CHIT1 concentrations in CSF are elevated compared to controls and significantly increase over 14 months of treatment with nusinersen. 16 Other potentially interesting biomarkers for SMA patients are the neurodegenerative markers neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH), which were also found to be elevated in ALS and correlated with disease progression. 17 A recent study in infants with SMA type 1 showed that pNfH was elevated in plasma and CSF, correlated with multiple indicators of disease severity, and rapidly declined after treatment initiation with nusinersen.…”

“…In amyotrophic lateral sclerosis (ALS), another motor neuron disease, studies showed that both CHIT1 and YKL‐40 were elevated in CSF and correlated with disease progression rate and a shorter survival 14,15 . No such data are currently available for individuals with SMA, except for a single recent study that concluded that baseline CHIT1 concentrations in CSF are elevated compared to controls and significantly increase over 14 months of treatment with nusinersen 16 …”

Glial fibrillary acidic protein in cerebrospinal fluid of patients with spinal muscular atrophy

“…In addition, chitotriosidase 1 concentrations in CSF (cCHIT1) were measured in the same cohort and at the same time as cGFAP (previously published in Ref. [ 22 ]).…”

“…cCHIT1 has recently been shown to be elevated in treatment‐naïve patients with SMA. 22 cNfL has been found to reflect disease severity and treatment response in pediatric SMA, 23 but still provides limited information in adult SMA because it overlaps with healthy controls and often shows no association with motor improvement. 24 , 25 , 26 , 27 …”