Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation

Baldassari, Laura E.; Planchon, Sarah M.; Bermel, Robert; Nakamura, Kunio; Fisher, Elizabeth; Feng, Jenny; Sakaie, Ken; Ontaneda, Daniel; Cohen, Jeffrey A.

doi:10.1177/2055217319887198

Cited by 8 publications

(5 citation statements)

References 37 publications

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“…The only report of in vivo effects of MSC on the levels of neurofilaments derived from a study where the stem cells were injected intravenously; similarly to our data, the authors of this trial did not detect significant changes in the serum levels of NF-L, following MSC-IV treatment. 14 …”

Section: Discussionmentioning

confidence: 99%

Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis

Petrou¹,

Kassis²,

Ginzberg³

et al. 2022

Stem Cells Translational Medicine

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Background Neurofilament light chains (NF-L) were shown to serve as a reliable biomarker of neurodegeneration in multiple sclerosis (MS). The chemokine receptor CXCL13 was shown to correlate with CNS inflammatory activity and to predict the future progression of MS. Objective To evaluate the levels of NF-L and CXCL13 in the cerebrospinal fluid (CSF) following treatment with mesenchymal stem cells (MSC) in patients with progressive MS. Methods The CSF samples were obtained from 48 patients with progressive MS who participated in a double-blind randomized phase II clinical trial that tested the effects of intrathecal (IT) or intravenous (IV) transplantation of mesenchymal stem cells (MSC), at baseline (before the first injection of the MSC) and at 6 months following treatment with MSC, or sham treatment. The CSF specimens were tested in a blinded way, using a single-molecule array (SIMOA) technique. Findings The CSF levels of NF-L were significantly lower at 6 months following treatment with MSC-IT when compared with the baseline, pre-treatment measurements (P = .026, Wilcoxon paired test). Nine out of 15 tested patients in the MSC-IT group had a reduction in NF-L levels of more than 50% (median decrease: −4449 pg/mL) when compared with 5/15 in the MSC-IV group (median decrease: −151 pg/mL) and 1/15 in the placebo group (median increase: +2450 pg/mL) (P = .001 for MSC-IT vs. placebo, chi-square test). CXCL13 levels were also reduced at 6 months following MSC-IT treatment but not to a statistically significant level. Conclusions Our findings indicate possible neuroprotective effects of MSC transplantation in patients with MS. Clinical trial registration NCT02166021

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Section: Discussionmentioning

confidence: 99%

Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis

Petrou¹,

Kassis²,

Ginzberg³

et al. 2022

Stem Cells Translational Medicine

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“…The other 18 studies that did not declare whether controls were age-matched were then considered as not age-matched studies, even though there was no statistical difference of age at baseline comparison in some studies. As to DMT use, 7 recruited treatment-naïve patients [ 10 , 28 , 32 , 35 , 36 , 42 , 46 ], while the other studies reported a proportion of patients treated with DMT or missing information of DMT use. Quality assessment using NOS for case-control studies identified 19 moderate-quality studies that had 5 or 6 stars and 9 high-quality studies with 7–9 stars ( S2 Table ).…”

Section: Resultsmentioning

confidence: 99%

Neurofilament light chain in blood as a diagnostic and predictive biomarker for multiple sclerosis: A systematic review and meta-analysis

Ning

Wang

2022

PLoS ONE

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Background Neurofilament light chain (NfL) in cerebrospinal fluid (CSF) is a biomarker of multiple sclerosis (MS). However, CSF sampling is invasive and has limited the clinical application. With the development of highly sensitive single-molecule assay, the accurate quantification of the very low NfL levels in blood become feasible. As evidence being accumulated, we performed a meta-analysis to evaluate the diagnostic and predictive value of blood NfL in MS patients. Methods We performed literature search on PubMed, EMBASE, Web of Science and Cochrane Library from inception to May 31, 2022. The blood NfL differences between MS vs. controls, MS vs. clinically isolated syndrome (CIS), progressive MS (PMS) vs. relapsing-remitting MS (RRMS), and MS in relapse vs. MS in remission were estimated by standard mean difference (SMD) and corresponding 95% confidence interval (CI). Pooled hazard ratio (HR) and 95%CI were calculated to predict time to reach Expanded Disability Status Scale (EDSS) score≥4.0 and to relapse. Results A total of 28 studies comprising 6545 MS patients and 2477 controls were eligible for meta-analysis of diagnosis value, and 5 studies with 4444 patients were synthesized in analysis of predictive value. Blood NfL levels were significantly higher in MS patients vs. age-matched controls (SMD = 0.64, 95%CI 0.44–0.85, P<0.001), vs. non-matched controls (SMD = 0.76, 95%CI 0.56–0.96, P<0.001) and vs. CIS patients (SMD = 0.30, 95%CI 0.18–0.42, P<0.001), in PMS vs. RRMS (SMD = 0.56, 95%CI 0.27–0.85, P<0.001), and in relapsed patients vs. remitted patients (SMD = 0.54, 95%CI 0.16–0.92, P = 0.005). Patients with high blood NfL levels had shorter time to reach EDSS score≥4.0 (HR = 2.36, 95%CI 1.32–4.21, P = 0.004) but similar time to relapse (HR = 1.32, 95%CI 0.90–1.93, P = 0.155) compared to those with low NfL levels. Conclusion As far as we know, this is the first meta-analysis evaluating the diagnosis and predictive value of blood NfL in MS. The present study indicates blood NfL may be a useful biomarker in diagnosing MS, distinguishing MS subtypes and predicting disease worsening in the future.

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“…35 While Petrou et al 8 have shown a reduction of CSF neurofilament following in PMS patients with active disease, other studies have shown no change in CSF-NfL after intrathecal MSC therapy 36 or serum NfL after IV MSCs. 37 MSC-NTF cells have been observed to decrease NfL and pNfH in ALS participants across 28 weeks. 19 Further studies are needed to determine the utility of CS-NfL and other neurodegenerative biomarkers as treatment outcome measures in PMS.…”

Section: Median Change From Baseline-clinical Efficacymentioning

confidence: 89%

Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis

et al. 2022

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Background: Autologous mesenchymal stem cell neurotrophic factor–secreting cells (NurOwn®) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS). Objective: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments. Methods: Eighteen participants with non-relapsing PMS were treated. The primary endpoint was safety. Secondary endpoints included: cerebrospinal fluid (CSF) biomarkers; timed 25-foot walk speed, nine-hole peg test (9-HPT), low-contrast letter acuity, symbol digit modalities test, and 12-item multiple sclerosis (MS) walking scale. Seventeen participants received all treatments. Results: No deaths/adverse events related to worsening of MS, clinical/magnetic resonance imaging (MRI) evidence of disease activation, and clinically significant changes in safety lab results were reported. Two participants developed symptoms of low back and leg pain, consistent with a diagnosis of arachnoiditis, occurring in one of three intrathecal treatments in both participants. Nineteen percent of treated participants achieved pre-specified ⩾ 25% improvements in timed 25-foot walk speed/nine-HPT at 28 weeks compared to baseline, along with consistent efficacy signals for pre-specified response criteria across other secondary efficacy outcomes. CSF neuroprotective factors increased, and inflammatory biomarkers decreased after treatment, consistent with the proposed mechanism of action. Conclusion: Based on these encouraging preliminary findings, further confirmation in a randomized study is warranted.

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Serum neurofilament light chain concentration in a phase 1/2 trial of autologous mesenchymal stem cell transplantation

Cited by 8 publications

References 37 publications

Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis

Effects of Mesenchymal Stem Cell Transplantation on Cerebrospinal Fluid Biomarkers in Progressive Multiple Sclerosis

Neurofilament light chain in blood as a diagnostic and predictive biomarker for multiple sclerosis: A systematic review and meta-analysis

Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis

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