Universität zu Köln

Schorling, David C., Koelbel, Heike, Hentschel, Andreas, Pechmann, Astrid, Meyer, Nancy, Wirth, Brunhilde, Rombo, Roman, Sickmann, Albert, Kirschner, Janbernd ORCID: 0000-0003-1618-7386, Schara-Schmidt, Ulrike, Lochmuller, Hanns and Roos, Andreas (2022). Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy. Eur. J. Neurol., 29 (7). S. 2084 - 2097. HOBOKEN: WILEY. ISSN 1468-1331

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Abstract

Background and purpose The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision-making remains challenging, underlining the persistent need for validated biomarkers. Methods We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme-linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0-16 years) revealed a significant decline of cathepsin D levels in SMA patients aged >= 2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of treatment responders than in nonresponders. We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schorling, David C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koelbel, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Hentschel, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Pechmann, Astrid UNSPECIFIED UNSPECIFIED UNSPECIFIED Meyer, Nancy UNSPECIFIED UNSPECIFIED UNSPECIFIED Wirth, Brunhilde UNSPECIFIED UNSPECIFIED UNSPECIFIED Rombo, Roman UNSPECIFIED UNSPECIFIED UNSPECIFIED Sickmann, Albert UNSPECIFIED UNSPECIFIED UNSPECIFIED Kirschner, Janbernd UNSPECIFIED orcid.org/0000-0003-1618-7386 UNSPECIFIED Schara-Schmidt, Ulrike UNSPECIFIED UNSPECIFIED UNSPECIFIED Lochmuller, Hanns UNSPECIFIED UNSPECIFIED UNSPECIFIED Roos, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-691536
DOI:	10.1111/ene.15331
Journal or Publication Title:	Eur. J. Neurol.
Volume:	29
Number:	7
Page Range:	S. 2084 - 2097
Date:	2022
Publisher:	WILEY
Place of Publication:	HOBOKEN
ISSN:	1468-1331
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language SHAM CONTROL; SMN GENE; NEUROFILAMENT; ACTIVATION Multiple languages Clinical Neurology; Neurosciences Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69153