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...
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-07-01
|
| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-021-01961-8 |
| _version_ | 1831545533253025792 |
|---|---|
| author | Maren Freigang Petra Steinacker Claudia Diana Wurster Olivia Schreiber-Katz Alma Osmanovic Susanne Petri Jan Christoph Koch Kevin Rostásy Björn Falkenburger Albert Christian Ludolph Markus Otto Andreas Hermann René Günther |
| author_facet | Maren Freigang Petra Steinacker Claudia Diana Wurster Olivia Schreiber-Katz Alma Osmanovic Susanne Petri Jan Christoph Koch Kevin Rostásy Björn Falkenburger Albert Christian Ludolph Markus Otto Andreas Hermann René Günther |
| author_sort | Maren Freigang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-17T01:29:21Z |
| format | Article |
| id | doaj.art-0cde2deffee34edd83dfefc691547d42 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-12-17T01:29:21Z |
| publishDate | 2021-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-0cde2deffee34edd83dfefc691547d422022-12-21T22:08:37ZengBMCOrphanet Journal of Rare Diseases1750-11722021-07-0116111110.1186/s13023-021-01961-8Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophyMaren Freigang0Petra Steinacker1Claudia Diana Wurster2Olivia Schreiber-Katz3Alma Osmanovic4Susanne Petri5Jan Christoph Koch6Kevin Rostásy7Björn Falkenburger8Albert Christian Ludolph9Markus Otto10Andreas Hermann11René Günther12Department of Neurology, Technische Universität DresdenDepartment of Neurology, Ulm UniversityDepartment of Neurology, Ulm UniversityDepartment of Neurology, Hannover Medical SchoolDepartment of Neurology, Hannover Medical SchoolDepartment of Neurology, Hannover Medical SchoolDepartment of Neurology, University Medicine GöttingenDepartment of Pediatric Neurology, Children’s Hospital Datteln, University Witten/HerdeckeDepartment of Neurology, Technische Universität DresdenDepartment of Neurology, Ulm UniversityDepartment of Neurology, Ulm UniversityTranslational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, University of RostockDepartment of Neurology, Technische Universität DresdenAbstract 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.https://doi.org/10.1186/s13023-021-01961-8SMAChitotriosidase 1BiomarkerNusinersenASO |
| spellingShingle | Maren Freigang Petra Steinacker Claudia Diana Wurster Olivia Schreiber-Katz Alma Osmanovic Susanne Petri Jan Christoph Koch Kevin Rostásy Björn Falkenburger Albert Christian Ludolph Markus Otto Andreas Hermann René Günther Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy Orphanet Journal of Rare Diseases SMA Chitotriosidase 1 Biomarker Nusinersen ASO |
| title | Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy |
| title_full | Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy |
| title_fullStr | Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy |
| title_full_unstemmed | Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy |
| title_short | Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy |
| title_sort | increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy |
| topic | SMA Chitotriosidase 1 Biomarker Nusinersen ASO |
| url | https://doi.org/10.1186/s13023-021-01961-8 |
| work_keys_str_mv | AT marenfreigang increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT petrasteinacker increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT claudiadianawurster increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT oliviaschreiberkatz increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT almaosmanovic increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT susannepetri increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT janchristophkoch increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT kevinrostasy increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT bjornfalkenburger increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT albertchristianludolph increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT markusotto increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT andreashermann increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy AT renegunther increasedchitotriosidase1concentrationfollowingnusinersentreatmentinspinalmuscularatrophy |