Unusual inclusions in cerebrospinal fluid macrophages of spinal muscular atrophy patients treated with nusinersen

Machacek, Miranda; Gogakos, Tasos; Fletcher, Madeline C; Lunderville, Kathryn A; Swoboda, Kathryn J.; Sohani, Aliyah R.

doi:10.1111/ijlh.13392

Cited by 8 publications

(5 citation statements)

References 11 publications

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“…In the course of treatment, we observed monocytic cells with indefinable, unspecified inclusions within the nusinersen-treated cohort of Dresden. Consistent with that, recently published research [47,48] of two independent research groups reported the emergence of unusual macrophages with specific inclusions, which could be detected beginning from the second lumbar puncture and notably were not present before initiation of nusinersen treatment. These macrophages-labeled 'nusinophages'-were present in all investigated patients for at least one time during 14 months of nusinersen treatment and were not found in patients with repeated lumbar puncture without nusinersen administration, which leads to the assumption that the inclusions inside these macrophages may contain nusinersen or nusinersen metabolites.…”

Section: Discussionsupporting

confidence: 82%

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

Freigang

Steinacker

Wurster

et al. 2021

Orphanet J Rare Dis

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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.

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Section: Discussionsupporting

confidence: 82%

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

Freigang

Steinacker

Wurster

et al. 2021

Orphanet J Rare Dis

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“…After publication of the seminal report by Gingele et al [8] in July 2019 (a study of 19 adults, 8 with SMA type 2 and 11 with type 3), we observed these macrophages in 3 other pediatric patients with SMA type 1 described below. Since that time, similar macrophages were documented in 2 infants with SMA type 1, published online in November 2020 [9].…”

Section: Introductionsupporting

confidence: 52%

“…Nusinersen is not packaged into a chemical or nanoparticle delivery system known to cause macrophage inclusions to get it across the blood-brain barrier [9]. Instead, the intrathecal "drug" is nusinersen heptadecasodium dissolved in formulated artificial CSF without any preservatives [5][6][7].…”

Section: Discussion/conclusionmentioning

confidence: 99%

Cytochemical Characterization of Cerebrospinal Fluid Macrophage Inclusions in Pediatric Patients Receiving Intrathecal Nusinersen (SPINRAZA®) for Spinal Muscular Atrophy

et al. 2021

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Introduction: Spinal muscular atrophy (SMA) is a debilitating neuromuscular disorder caused by biallelic deletion of the SMN1 gene. Nusinersen, an antisense oligonucleotide delivered intrathecally, binds to the pre-mRNA of SMN1’s pseudogene, SMN2, to prevent exon skipping and produce functional SMN protein to compensate for the deficiency caused by SMN1 deletion. Case Presentation: We reviewed 15 cerebrospinal fluid (CSF) cytology specimens from 8 patients receiving nusinersen for SMA. Macrophages with peculiar inclusions (“nusinophages”) were seen in 8 specimens from 4 of the patients: 1 infant and 3 children with SMA type 1. This finding has only previously been reported in adults with SMA types 2 and 3 and in 2 infants with SMA type 1. Discussion/Conclusion: Specimens containing nusinophages had a significantly higher proportion of macrophages and lower proportion of lymphocytes than those in which nusinophages were not detected. The macrophage inclusions do not represent iron or microorganisms and instead are composed, at least in part, of glycosaminoglycans. Because CSF is a common specimen type, cytotechnologists and cytopathologists need to be aware of these inclusions, so they do not interpret them erroneously as evidence of infection or hemorrhage, especially in light of the fact that oligonucleotide therapy has been approved for a variety of conditions and is currently under investigation for intrathecal delivery in several other neurodegenerative disorders.

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“…On the other hand, two studies described unusual inclusions in CSF macrophages called 'nusinophages'. Gingele et al [43] hypothesized that these granular inclusions could contain nusinersen, while Miranda et al [44] suggested that the vacuoles and inclusions are due to macrophage activation and cytokine accumulation. Immunostimulatory effects have been previously associated with a large number of ASOs through different mechanisms: the base-pair sequence and the backbone chemistry of these drugs are recognized by nucleic acid-sensing TLR receptors inducing a drug-specific immune response [45]; moreover, ASOs directly act on lymphoid cells causing them to produce proinflammatory cytokines, such as TNF-α and interferon-γ, and consequently, IgG and IgM against auto-and hetero-antigens [46].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal Fluid and Clinical Profiles in Adult Type 2–3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience

et al. 2021

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Background and Objectives Nusinersen was approved as the first disease-modifying therapy in spinal muscular atrophy (SMA). Our aim was to analyse therapy-related changes in cerebrospinal fluid (CSF) and serum parameters of adult type 2–3 SMA and to correlate biochemical data with motor functional status. Methods Nine adult SMA type 2–3 patients and ten control subjects without neurodegenerative diseases were included in our single-centre study. Cross-sectional analysis of CSF routine parameters, CSF neurofilament light chain, CSF Tau, CSF phospho-Tau and serum creatinine was performed between SMA patients at baseline (T0) and control subjects. The above-mentioned fluid parameters were longitudinally analysed in the SMA cohort after loading dose (T1) and after four maintenance doses (T2, T3, T4, T5). Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM) and the 6-minute walking test (6MWT) were used to evaluate motor outcomes. Results Improvements in HFMSE, RULM and 6MWT were observed only after the loading dose of nusinersen. No significant differences in routine CSF parameters and CSF markers of neurodegeneration were found between SMA patients and control subjects. Serum creatinine levels were significantly lower in SMA patients than in control subjects. CSF/serum albumin ratio (Qalb) significantly increased from T0 to each time point, without any further increase after the maintenance doses. Persistent systemic oligoclonal bands (OCBs) were found in five patients from baseline. Three more patients developed persistent systemic OCBs from T1; one patient showed intrathecal OCBSs from baseline to T5. Markers of neurodegeneration did not change during the follow-up and did not correlate with motor scores at baseline and at each timepoint. Serum creatinine levels significantly correlated with HFMSE and RULM at each time point. Conclusions The increase of the Qalb values and the development of systemic OCBs in some SMA patients could be due to repeated lumbar puncture and to the immunogenic effect of nusinersen. On the other hand, the presence of OCBs in serum and/or CSF at baseline should be further investigated. Furthermore, biomarkers of neurodegeneration did not play a prognostic role in our cohort of adult SMA patients. Supplementary Information The online version contains supplementary material available at 10.1007/s40261-021-01071-0.

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Unusual inclusions in cerebrospinal fluid macrophages of spinal muscular atrophy patients treated with nusinersen

Cited by 8 publications

References 11 publications

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

Cytochemical Characterization of Cerebrospinal Fluid Macrophage Inclusions in Pediatric Patients Receiving Intrathecal Nusinersen (SPINRAZA®) for Spinal Muscular Atrophy

Cerebrospinal Fluid and Clinical Profiles in Adult Type 2–3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience

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