Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment

Wurster, Claudia D.; Günther, René; Steinacker, Petra; Dreyhaupt, Jens; Wollinsky, K. H.; Uzelac, Zeljko; Witzel, Simon; Kocak, Tugrul; Winter, Benedikt; Koch, Jan Christoph; Lingor, Paul; Petri, Susanne; Ludolph, Albert C.; Hermann, Andreas; Otto, Markus

doi:10.1177/1756286419846058

Cited by 52 publications

(53 citation statements)

References 28 publications

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“…Total protein concentrations were increased (0.441 vs. 0.372 g/L; p < .01) in the SMA patient group after 10 months of nusinersen treatment compared with the pre‐treatment condition (Table ; Figure S1a). There was also a trend toward an increased Q alb after nusinersen treatment as reported recently (Wurster, Günther, et al, ). However, this increase did not reach the level of significance in our patient cohort ( p = .07).…”

Section: Resultssupporting

confidence: 84%

“…Plasma pNfH was recently described as a potential marker of disease activity and treatment response in infants with SMA 1 (Darras, Crawford, et al, ). In contrast, another recent study provided evidence that CSF concentrations of neurofilament light chain (NfL) and pNfH are neither elevated in adolescent or adult SMA 2 and SMA 3 patients compared with controls nor influenced by the loading dosing of nusinersen (treatment day 63) (Wurster, Günther, et al, ). Hence, the authors of the latter work concluded that CSF neurofilament concentrations would not be useful as diagnostic or monitoring markers in adolescent/adult SMA 2 or 3 (Wurster, Günther, et al, ).…”

Section: Discussionmentioning

confidence: 99%

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Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

Keßler

Latzer

Schmid

et al. 2020

Journal of Neurochemistry

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This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abbreviations: ABC, ammonium bicarbonate; ACN, acetonitrile; ALSFRS-R, amyotrophic lateral sclerosis functional rating scale-revised; APC, absolute protein cluster; ASO, antisense oligonucleotide; CDH18, cadherin 18; COL6A1, collagen type VI alpha 1; CPE, carboxypeptidase E; CSF, cerebrospinal fluid; DDA, data-dependent acquisition; DPC, differential protein cluster; DTT, dithiothreitol; EMA, European Medicines Agency; FDA, U.S. Food and Drug Administration; HFMSE, hammersmith functional rating scale expanded; IAA, iodoacetamide; IgG, immunoglobulin G; IPA, ingenuity pathway analysis; IQR, interquartile range; LFQ, label-free quantification; MS, mass spectrometry; N/A, not applicable; NPTX1, neuronal pentraxin-1; OCB, oligoclonal immunoglobulin G (IgG) bands; PARK7, Parkinson's disease protein 7; PCA, principle component analysis; pNfH, plasma phosphorylated neurofilament heavy chain; Q alb , CSF/ serum quotients of albumin; rpm, rounds per minute; RRID, Research Resource Identifier (see scicrunch.org); SEM, standard error of the mean; SEMA7A, semaphorin 7A; SMA, 5q-linked spinal muscular atrophy; SMN1, survival motor neuron 1 gene; SMN2, survival motor neuron 2 gene; T 0 , first nusinersen injection at baseline; T 10 , sixth nusinersen injection after 10 months; TFA, trifluoracetic acid; WPCNA, weighted protein correlation network analysis; ΔHFMSE (T 0 -T 10 ), change in Hammersmith Functional Rating Scale Expanded score between T 0 and T 10 . AbstractPromising results from recent clinical trials on the approved antisense oligonucleotide nusinersen in pediatric patients with 5q-linked spinal muscular atrophy (SMA) still have to be confirmed in adult patients but are hindered by a lack of sensitive biomarkers that indicate an early therapeutic response. Changes in the overall neurochemical composition of cerebrospinal fluid (CSF) under therapy may yield additive diagnostic and predictive information. With this prospective proof-of-concept and feasibility study, we evaluated non-targeted CSF proteomic profiles by mass spectrometry along with basic CSF parameters of 10 adult patients with SMA types 2 or 3 before and after 10 months of nusinersen therapy, in comparison with 10 age-and gender-matched controls. These data were analyzed by bioinformatics and correlated with clinical outcomes assessed by the Hammersmith Functional Rating Scale Expanded (HFMSE). CSF proteomic profiles of SMA patients differed from controls. Two groups of SMA patients were identified based on unsupervised clustering. These groups differed in age and expression of proteins related to neurodegeneration and neuroregeneration. Intraindividual CSF differences in response to nusinersen treatment varied between patients who clinically improved and those who did not. Data are available via P...

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Section: Resultssupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

Keßler

Latzer

Schmid

et al. 2020

Journal of Neurochemistry

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“…Overall, the selection of these biomarkers is based on the results of previous studies with neurodegenerative diseases. pNfH has been shown to be a reliable marker in motor neuron diseases, such as amyotrophic lateral sclerosis and SMA type 1 and 2 [15], but not in adult SMA3 [17]. The elevation of pNfH indicates an axonal loss and a correlation between neurofilament level and disease progression is suspected [15,18].…”

Section: Laboratory Testingmentioning

confidence: 99%

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study

Walter¹,

Wenninger²,

Thiele³

et al. 2019

Journal of Neuromuscular Diseases

155

167

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Objective: Spinal muscular atrophy (SMA) is a progressive autosomal recessive motor neuron disease caused by loss of the SMN1 gene. Based on randomized clinical trials in children with SMA type 1 and 2, Nusinersen has been approved as the first treatment for all types of SMA, including adults with SMA type 3. Methods: We evaluated the safety and treatment effects of Nusinersen in longstanding adult 5q-SMA type 3. Patients were treated with intrathecal loading doses at day 1, 14, 28 and 63, followed by maintenance dose every four months up to 300 days. We monitored the patients within SMArtCARE, a prospective open-label outcome study for disease progression, side effects and treatment efficacy, encompassing clinical examination including MRC sum score, vital capacity in sitting position (VC, VC %pred.), ALS Functional Rating Scale (ALS-FRS), 6-Minute-Walk-Test (6MWT), Revised Upper Limb Module (RULM), and Hammersmith Functional Rating Scale (HFMSE). We also measured biomarkers in the spinal fluid (phosphorylated neurofilament heavy chain pNFH, neuron-specific enolase NSE, proteins, ß-Amyloid 1-40, ß-Amyloid 1-42, tau and phospho-tau) and creatine kinase (CK). Assessments were performed at baseline, day 63 (V4), day 180 (V5) and day 300 (V6). For statistical analysis, we compared baseline to V4, V5 and V6, using the paired sample t-test. When there were significant differences, we added cohen´s d and effect size r for evaluation of clinical meaningfulness. 1 Equal contribution.

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“…That brought the idea of using antisense oligonucleotide, which blocks the intronic splicing silencer binding site at exon 7, leading to an increase in SMN protein levels in motor neurons (Figure c and d) (Bennett, Baker, Pham, Swayze, & Geary, ; Wurster & Ludolph, ). This particular 18 nucleotides long antisense oligonucleotide is called nusinersen that has been approved by the Federal Drugs Administration as well as European Medicines Agency as the disease modifying treatment for SMA and commercially available as “Spinraza.” However, because of the inability to cross blood‒brain barrier, nusinersen is administered intrathecally in patients (Stolte et al, ; Wurster, Gunther, et al, ). Long‐term treatment of nusinersen is found to alleviate SMA disease symptoms and improve lifestyle in patients suffering from SMA1 and SMA2.…”

Section: Therapy For Smamentioning

confidence: 99%

The light at the end of the tunnel gets vivid for spinal muscular atrophy

Dutta

Chandra

Mohanakumar

2020

Journal of Neurochemistry

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Kessler et al. in this current issue have attempted to discern biomarker(s) for spinal muscular atrophy (SMA) by assessing alterations in cerebrospinal fluid (CSF) proteomics profile. Recently, antisense oligonucleotide (nusinersen) therapy is shown to mitigate pathologies and provide behavioral improvements in patients. This Editorial highlights the study by Kessler et al on the proteomics of CSF from adult and young patients prior to, and 10 months after nusinersen intrathecal therapy. Although the study by Kessler et al. suffers from small sample size and mixed results that deterred a strong conclusion, yet is a strong case‒control study that is contemporary and important to the patients, clinicians and care‐takers alike. Since identifying biomarker and characterizing the pathology in SMA are imminent necessity to advance this promising therapy, the high‐throughput CSF proteomics data prior and after nusinersen therapy provide possible biomarkers that may help in identification of positive responders, the disease course, efficacy of treatment, and more accurate prognosis.

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Neurochemical markers in CSF of adolescent and adult SMA patients undergoing nusinersen treatment

Cited by 52 publications

References 28 publications

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

Cerebrospinal fluid proteomic profiling in nusinersen‐treated patients with spinal muscular atrophy

Safety and Treatment Effects of Nusinersen in Longstanding Adult 5q-SMA Type 3 – A Prospective Observational Study

The light at the end of the tunnel gets vivid for spinal muscular atrophy

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