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      Increased chitotriosidase 1 concentration following nusinersen treatment in spinal muscular atrophy

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          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.

          Supplementary Information

          The online version contains supplementary material available at 10.1186/s13023-021-01961-8.

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          Most cited references53

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          Statistics corner: A guide to appropriate use of correlation coefficient in medical research.

          M M Mukaka (2012)
          Correlation is a statistical method used to assess a possible linear association between two continuous variables. It is simple both to calculate and to interpret. However, misuse of correlation is so common among researchers that some statisticians have wished that the method had never been devised at all. The aim of this article is to provide a guide to appropriate use of correlation in medical research and to highlight some misuse. Examples of the applications of the correlation coefficient have been provided using data from statistical simulations as well as real data. Rule of thumb for interpreting size of a correlation coefficient has been provided.
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            Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

            New England Journal of Medicine, 377(18), 1723-1732
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              Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

              Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).
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                Author and article information

                Contributors
                rene.guenther@uniklinikum-dresden.de
                Journal
                Orphanet J Rare Dis
                Orphanet J Rare Dis
                Orphanet Journal of Rare Diseases
                BioMed Central (London )
                1750-1172
                28 July 2021
                28 July 2021
                2021
                : 16
                : 330
                Affiliations
                [1 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, Department of Neurology, , Technische Universität Dresden, ; Dresden, Germany
                [2 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Department of Neurology, , Ulm University, ; Ulm, Germany
                [3 ]GRID grid.10423.34, ISNI 0000 0000 9529 9877, Department of Neurology, , Hannover Medical School, ; Hannover, Germany
                [4 ]GRID grid.411984.1, ISNI 0000 0001 0482 5331, Department of Neurology, , University Medicine Göttingen, ; Göttingen, Germany
                [5 ]GRID grid.412581.b, ISNI 0000 0000 9024 6397, Department of Pediatric Neurology, , Children’s Hospital Datteln, University Witten/Herdecke, ; Datteln, Germany
                [6 ]GRID grid.424247.3, ISNI 0000 0004 0438 0426, German Center for Neurodegenerative Diseases (DZNE) Dresden, ; Dresden, Germany
                [7 ]GRID grid.424247.3, ISNI 0000 0004 0438 0426, German Center for Neurodegenerative Diseases (DZNE) Ulm, ; Ulm, Germany
                [8 ]GRID grid.10493.3f, ISNI 0000000121858338, Translational Neurodegeneration Section “Albrecht-Kossel”, Department of Neurology, University Medical Center Rostock, , University of Rostock, ; Rostock, Germany
                [9 ]German Center for Neurodegenerative Diseases (DZNE) Rostock/Greifswald, Rostock, Germany
                Author information
                http://orcid.org/0000-0003-0329-5644
                Article
                1961
                10.1186/s13023-021-01961-8
                8320162
                34321067
                5ef00fae-f0d4-468a-8006-f56cdfb24730
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                History
                : 27 May 2021
                : 18 July 2021
                Funding
                Funded by: Technische Universität Dresden (1019)
                Categories
                Research
                Custom metadata
                © The Author(s) 2021

                Infectious disease & Microbiology
                sma,chitotriosidase 1,biomarker,nusinersen,aso
                Infectious disease & Microbiology
                sma, chitotriosidase 1, biomarker, nusinersen, aso

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