Summary of Study ST002858
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001789. The data can be accessed directly via it's Project DOI: 10.21228/M8G43R This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST002858 |
| Study Title | Intracerebroventricular Transplantation of Foetal Allogeneic Neural Stem Cells in Patients with Secondary Progressive Multiple Sclerosis (hNSC-SPMS): a phase I dose-escalation clinical trial - Metabolomics Analysis of Human Serum |
| Study Summary | This is an open-label, first-in-human, dose-escalation phase I study (NCT03282760, EudraCT2015‐004855‐37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of progressive multiple sclerosis. We report the analysis of 1 year of data from the first cohort of 15 patients from two trial sites that received increasing numbers of allogeneic hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed over the 12-month follow-up. Participants displayed stability of clinical and laboratory parameters, as well as lesion load and activity at the brain MRIs, compared to study entry. Longitudinal metabolomics and lipidomics analyses of cerebrospinal fluid and serum from these patients identified time and dose-dependent responses, with increased levels of free fatty acids and acylcarnitines in the CSF, especially at the highest dose of injected hNSCs at the one-year follow-up time point. Finally, a significant inverse correlation was found between the highest dose of injected hNSCs and the smaller parenchymal brain volume change (PBVC; Spearman’s rho= -0.7, p= 0.03), clinical covariates that correlated with CSF levels of free fatty acids, acyl-carnitines, oxylipins, conjugated bile acids and purine breakdown and deamination products, such as hypoxanthine. The absence of AEs and the stability of functional and structural outcomes is reassuring in terms of risks and represent a main milestone to rigorously address the challenges for the safe translation of key principles of stem cell biology into effective regenerative medicines. |
| Institute | University of Colorado Anschutz Medical Campus |
| Last Name | Stephenson |
| First Name | Daniel |
| Address | Research 1 South L18-1303 12801 E. 17th Ave., Aurora, Colorado, 80045, USA |
| daniel.stephenson@cuanschutz.edu | |
| Phone | 303-724-3339 |
| Submit Date | 2023-09-11 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | mzXML |
| Analysis Type Detail | GC/LC-MS |
| Release Date | 2023-09-27 |
| Release Version | 1 |
Select appropriate tab below to view additional metadata details:
Project:
| Project ID: | PR001789 |
| Project DOI: | doi: 10.21228/M8G43R |
| Project Title: | Intracerebroventricular Transplantation of Foetal Allogeneic Neural Stem Cells in Patients with Secondary Progressive Multiple Sclerosis (hNSC-SPMS): a phase I dose-escalation clinical trial |
| Project Type: | MS untargeted analysis |
| Project Summary: | SUMMARY This is an open-label, first-in-human, dose-escalation phase I study (NCT03282760, EudraCT2015‐004855‐37) to determine the feasibility, safety, and tolerability of the transplantation of allogeneic human neural stem/progenitor cells (hNSCs) for the treatment of progressive multiple sclerosis. We report the analysis of 1 year of data from the first cohort of 15 patients from two trial sites that received increasing numbers of allogeneic hNSCs delivered via intracerebroventricular injection in combination with an immunosuppressive regimen. No treatment-related deaths nor serious adverse events (AEs) were observed over the 12-month follow-up. Participants displayed stability of clinical and laboratory parameters, as well as lesion load and activity at the brain MRIs, compared to study entry. Longitudinal metabolomics and lipidomics analyses of cerebrospinal fluid and serum from these patients identified time and dose-dependent responses, with increased levels of free fatty acids and acylcarnitines in the CSF, especially at the highest dose of injected hNSCs at the one-year follow-up time point. Finally, a significant inverse correlation was found between the highest dose of injected hNSCs and the smaller parenchymal brain volume change (PBVC; Spearman’s rho= -0.7, p= 0.03), clinical covariates that correlated with CSF levels of free fatty acids, acyl-carnitines, oxylipins, conjugated bile acids and purine breakdown and deamination products, such as hypoxanthine. The absence of AEs and the stability of functional and structural outcomes is reassuring in terms of risks and represent a main milestone to rigorously address the challenges for the safe translation of key principles of stem cell biology into effective regenerative medicines. |
| Institute: | University of Colorado |
| Department: | Department of Biochemistry and Molecular Genetics |
| Laboratory: | Angelo D’Alessandro |
| Last Name: | Stephenson |
| First Name: | Daniel |
| Address: | Research 1 South L18-1303 12801 E. 17th Ave., Aurora, Colorado, 80045, USA |
| Email: | daniel.stephenson@cuanschutz.edu |
| Phone: | 303-724-3339 |
Subject:
| Subject ID: | SU002970 |
| Subject Type: | Human |
| Subject Species: | Homo sapiens |
| Taxonomy ID: | 9606 |
| Gender: | Male and female |
Factors:
Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)
| mb_sample_id | local_sample_id | TIMEPOINT |
|---|---|---|
| SA308864 | DS1-123-135 | FU1 |
| SA308865 | DS1-123-091 | FU1 |
| SA308866 | DS1-123-140 | FU1 |
| SA308867 | DS1-123-034 | FU1 |
| SA308868 | DS1-123-104 | FU1 |
| SA308869 | DS1-123-047 | FU1 |
| SA308870 | DS1-123-098 | FU1 |
| SA308871 | DS1-123-056 | FU1 |
| SA308872 | DS1-123-054 | FU1 |
| SA308873 | DS1-123-023 | FU1 |
| SA308874 | DS1-123-069 | FU1 |
| SA308875 | DS1-123-075 | FU1 |
| SA308876 | DS1-123-006 | FU1 |
| SA308877 | DS1-123-147 | FU1 |
| SA308878 | DS1-123-009 | FU1 |
| SA308879 | DS1-123-113 | FU12 |
| SA308880 | DS1-123-090 | FU12 |
| SA308881 | DS1-123-048 | FU12 |
| SA308882 | DS1-123-045 | FU12 |
| SA308883 | DS1-123-086 | FU12 |
| SA308884 | DS1-123-137 | FU12 |
| SA308885 | DS1-123-149 | FU12 |
| SA308886 | DS1-123-064 | FU12 |
| SA308887 | DS1-123-026 | FU12 |
| SA308888 | DS1-123-059 | FU12 |
| SA308889 | DS1-123-030 | FU12 |
| SA308890 | DS1-123-088 | FU3 |
| SA308891 | DS1-123-129 | FU3 |
| SA308892 | DS1-123-152 | FU3 |
| SA308893 | DS1-123-153 | FU3 |
| SA308894 | DS1-123-155 | FU3 |
| SA308895 | DS1-123-150 | FU3 |
| SA308896 | DS1-123-143 | FU3 |
| SA308897 | DS1-123-096 | FU3 |
| SA308898 | DS1-123-119 | FU3 |
| SA308899 | DS1-123-138 | FU3 |
| SA308900 | DS1-123-092 | FU3 |
| SA308901 | DS1-123-078 | FU3 |
| SA308902 | DS1-123-012 | FU3 |
| SA308903 | DS1-123-061 | FU3 |
| SA308904 | DS1-123-053 | FU3 |
| SA308905 | DS1-123-033 | FU6 |
| SA308906 | DS1-123-084 | FU6 |
| SA308907 | DS1-123-121 | FU6 |
| SA308908 | DS1-123-128 | FU6 |
| SA308909 | DS1-123-108 | FU6 |
| SA308910 | DS1-123-036 | FU6 |
| SA308911 | DS1-123-044 | FU6 |
| SA308912 | DS1-123-065 | FU6 |
| SA308913 | DS1-123-068 | FU6 |
| SA308914 | DS1-123-017 | FU6 |
| SA308915 | DS1-123-010 | FU6 |
| SA308916 | DS1-123-120 | FU9 |
| SA308917 | DS1-123-020 | FU9 |
| SA308918 | DS1-123-156 | FU9 |
| SA308919 | DS1-123-154 | FU9 |
| SA308920 | DS1-123-151 | FU9 |
| SA308921 | DS1-123-126 | FU9 |
| SA308922 | DS1-123-112 | FU9 |
| SA308923 | DS1-123-055 | FU9 |
| SA308924 | DS1-123-060 | FU9 |
| SA308925 | DS1-123-062 | FU9 |
| SA308926 | DS1-123-095 | FU9 |
| SA308927 | DS1-123-066 | FU9 |
| SA308928 | DS1-123-022 | REND |
| SA308929 | DS1-123-029 | REND |
| SA308930 | DS1-123-041 | REND |
| SA308931 | DS1-123-079 | REND |
| SA308932 | DS1-123-019 | REND |
| SA308933 | DS1-123-077 | REND |
| SA308934 | DS1-123-008 | REND |
| SA308935 | DS1-123-144 | REND |
| SA308936 | DS1-123-074 | REND |
| SA308937 | DS1-123-132 | REND |
| SA308938 | DS1-123-110 | REND |
| SA308939 | DS1-123-122 | REND |
| SA308940 | DS1-123-097 | REND |
| SA308941 | DS1-123-049 | REND |
| SA308942 | DS1-123-101 | REND |
| SA308943 | DS1-123-004 | START |
| SA308944 | DS1-123-013 | START |
| SA308945 | DS1-123-040 | START |
| SA308946 | DS1-123-016 | START |
| SA308947 | DS1-123-107 | START |
| SA308948 | DS1-123-067 | START |
| SA308949 | DS1-123-038 | START |
| SA308950 | DS1-123-052 | START |
| SA308951 | DS1-123-089 | START |
| SA308952 | DS1-123-082 | START |
| SA308953 | DS1-123-024 | START |
| SA308954 | DS1-123-118 | START |
| SA308955 | DS1-123-115 | START |
| SA308956 | DS1-123-141 | START |
| SA308957 | DS1-123-002 | START |
| Showing results 1 to 94 of 94 |
Collection:
| Collection ID: | CO002963 |
| Collection Summary: | lumbar puncture for serum and CSF collection (stored at -80°C) |
| Sample Type: | Serum |
Treatment:
| Treatment ID: | TR002979 |
| Treatment Summary: | A total of 180 candidates volunteered between September 26, 2017, and January 13, 2020. The study was conducted in three centers. Two Italian centers, the ‘IRCCS Casa Sollievo della Sofferenza’ Research Hospital (Site 1) and the ‘Santa Maria di Terni’ Hospital (Site 2) recruited patients and performed the MRI examinations. The Multiple Sclerosis Centre of the Neurocentre of Southern Switzerland (Site 3) performed the magnetic resonance imaging (MRI) analysis. The ICVI of the ACT was performed at Site 2. Screening was done one month prior to enrolment in the study. The run-in period started after the screening examination (Run-in-START) and lasted three months (Run-in-END). After screening in the two recruiting centers (as above), n= 15 subjects with active and non-active SPMS suffering from progressive disability were found to be eligible, consented, and were assigned a unique identification number. Participants, nine females and six males, had a mean age of 50 years (range: 38–57), and were recruited in similar proportions by the two study sites. The mean EDSS was 7.6 (range 7–8), mean disease duration was 23 years (range 14–30), and mean time from diagnosis to secondary progression was 10 years (range: 1–20). The hNSC-SPMS study was advertised using the website of the hospitals and social media (eg Facebook and Twitter). The first patient selection was performed based on the documentation provided. Selected patients were then summoned in Site 1 and Site 2 (as above) for a first pre-screening meeting with the clinicians. Patients who agreed to participate were then subjected to the screening visit for the clinical trial. Following the surgical procedure, follow-up visits were performed monthly up to 12 months. Before transplantation, all patients underwent the following examinations (at both Run-in-START and Run-in-END): physical and neurological exams; vital signs; pregnancy tests (in fertile women); haematological and urine tests; lumbar puncture for serum and CSF collection (stored at -80°C); |
Sample Preparation:
| Sampleprep ID: | SP002976 |
| Sampleprep Summary: | Extraction of metabolites and lipids from serum and cerebrospinal fluid (CSF) was as follows: 40 µL CSF or serum was aliquoted into 2mL deep well plates followed by an addition of 360 µL cold MeOH:MeCN:H2O (5:3:2, v:v:v). Plates were then placed on a shaker at 4°C and plate shaker was set to 400 RPM for 30 minutes. Insoluble material was pelleted by centrifugation (4000 RPM, 10 min) and supernatants were isolated for analysis by UHPLC-MS. All 96-well plate pipetting was done using Integra MINI 96 (Integra Biosciences). |
Combined analysis:
| Analysis ID | AN004684 | AN004685 | AN004686 | AN004687 | AN004688 |
|---|---|---|---|---|---|
| Analysis type | MS | MS | MS | MS | MS |
| Chromatography type | Reversed phase | Reversed phase | Reversed phase | Reversed phase | Reversed phase |
| Chromatography system | Thermo Vanquish | Thermo Vanquish | Thermo Vanquish | Thermo Vanquish | Thermo Vanquish |
| Column | Phenomenex Kinetex C18 (150 x 2.1mm,1.7um) | Phenomenex Kinetex C18 (150 x 2.1mm,1.7um) | Phenomenex Kinetex C18 (30 x 2.1mm, 1.7um) | Phenomenex Kinetex C18 (30 x 2.1mm, 1.7um) | Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) |
| MS Type | ESI | ESI | ESI | ESI | EI |
| MS instrument type | Orbitrap | Orbitrap | Orbitrap | Orbitrap | Orbitrap |
| MS instrument name | Thermo Orbitrap Exploris 120 | Thermo Orbitrap Exploris 120 | Thermo Q Exactive Orbitrap | Thermo Q Exactive Orbitrap | Thermo Q Exactive Orbitrap |
| Ion Mode | POSITIVE | NEGATIVE | POSITIVE | NEGATIVE | NEGATIVE |
| Units | Peak area | Peak area | Peak area | Peak area | Peak area |
Chromatography:
| Chromatography ID: | CH003526 |
| Chromatography Summary: | Metabolomics Positive |
| Instrument Name: | Thermo Vanquish |
| Column Name: | Phenomenex Kinetex C18 (150 x 2.1mm,1.7um) |
| Column Temperature: | 45 |
| Flow Gradient: | 0 min - 0.45 ml/min - 5% B, 0.5 min - 0.45ml/min - 5% B, 1.1 min - 0.45ml/min - 95% B, 2.75 min - 0.45ml/min - 95% B, 3 min - 0.45ml/min - 5% B, 5min - 0.45ml/min - 5%B |
| Flow Rate: | 0.45 ml/min |
| Solvent A: | 0.1% Formic Acid in Water |
| Solvent B: | 0.1% Formic Acid in ACN |
| Chromatography Type: | Reversed phase |
| Chromatography ID: | CH003527 |
| Chromatography Summary: | Metabolomics Negative |
| Instrument Name: | Thermo Vanquish |
| Column Name: | Phenomenex Kinetex C18 (150 x 2.1mm,1.7um) |
| Column Temperature: | 45 |
| Flow Gradient: | 0 min - 0.45 ml/min - 0% B, 0.5 min - 0.45ml/min - 0% B, 1.1 min - 0.45ml/min - 100% B, 2.75 min - 0.45ml/min - 100% B, 3 min - 0.45ml/min - 0% B, 5min - 0.45ml/min - 0%B |
| Flow Rate: | 0.45 ml/min |
| Solvent A: | 5% ACN 95% Water 1mM Ammonium Acetate |
| Solvent B: | 95% ACN 5% Water 1mM Ammonium Acetate |
| Chromatography Type: | Reversed phase |
| Chromatography ID: | CH003528 |
| Chromatography Summary: | Lipidomics Positive |
| Instrument Name: | Thermo Vanquish |
| Column Name: | Phenomenex Kinetex C18 (30 x 2.1mm, 1.7um) |
| Column Temperature: | 50 |
| Flow Gradient: | 0 min - 0.3ml/min - 30%B, 3 min - 0.3ml/min - 100%B, 4.2min - 0.3ml/min - 100%B, 4.3min - 0.4ml/min - 30%B, 4.9min - 0/4ml/min - 30%B, 5 min - 0.3ml/min 30%B |
| Flow Rate: | 0.3-0.4ml/min |
| Solvent A: | 75:25 H2O:ACN 5mM NH4OAc |
| Solvent B: | 90:10 iPrOH:ACN 5mM NH4OAc |
| Chromatography Type: | Reversed phase |
| Chromatography ID: | CH003529 |
| Chromatography Summary: | Lipidomics Negative |
| Instrument Name: | Thermo Vanquish |
| Column Name: | Phenomenex Kinetex C18 (30 x 2.1mm, 1.7um) |
| Column Temperature: | 50 |
| Flow Gradient: | 0 min - 0.3ml/min - 10%B, 3 min - 0.3ml/min - 95%B, 4.2min - 0.3ml/min - 95%B, 4.3min - 0.45ml/min - 10%B, 4.9min - 0.4ml/min - 10%B, 5 min - 0.3ml/min 10%B |
| Flow Rate: | 0.3-0.45ml/min |
| Solvent A: | 75:25 H2O:ACN 5mM NH4OAc |
| Solvent B: | 90:10 iPrOH:ACN 5mM NH4OAc |
| Chromatography Type: | Reversed phase |
| Chromatography ID: | CH003530 |
| Chromatography Summary: | Oxylipin Negative |
| Instrument Name: | Thermo Vanquish |
| Column Name: | Waters ACQUITY UPLC BEH C18 (100 x 2.1mm,1.7um) |
| Column Temperature: | 60 |
| Flow Gradient: | 0min - 0.35ml/min - 0%B, 0.5min - 0.35ml/min - 25%B, 1min - 0.35ml/min - 25%B, 2.5min - 0.35ml/min - 40%B, 2.6min -0.35ml/min - 55%B, 4.5min - 0.35ml/min - 70%B, 4.6min - 0.35ml/min - 100%B, 6min - 0.35ml/min - 100%B, 6.1min - 0.35ml/min - 0%B, 7min - 0.35ml/min 0%B |
| Flow Rate: | 0.35ml/min |
| Solvent A: | 20:80:0.02 ACN:Water:Formic Acid |
| Solvent B: | 20:80:0.02 ACN:IPA:Formic Acid |
| Chromatography Type: | Reversed phase |
MS:
| MS ID: | MS004431 |
| Analysis ID: | AN004684 |
| Instrument Name: | Thermo Orbitrap Exploris 120 |
| Instrument Type: | Orbitrap |
| MS Type: | ESI |
| MS Comments: | Software for Feature Assignments - El-Maven |
| Ion Mode: | POSITIVE |
| MS ID: | MS004432 |
| Analysis ID: | AN004685 |
| Instrument Name: | Thermo Orbitrap Exploris 120 |
| Instrument Type: | Orbitrap |
| MS Type: | ESI |
| MS Comments: | Software for Feature Assignments - El-Maven |
| Ion Mode: | NEGATIVE |
| MS ID: | MS004433 |
| Analysis ID: | AN004686 |
| Instrument Name: | Thermo Q Exactive Orbitrap |
| Instrument Type: | Orbitrap |
| MS Type: | ESI |
| MS Comments: | Software for Feature Assignments - LipidSearch |
| Ion Mode: | POSITIVE |
| MS ID: | MS004434 |
| Analysis ID: | AN004687 |
| Instrument Name: | Thermo Q Exactive Orbitrap |
| Instrument Type: | Orbitrap |
| MS Type: | ESI |
| MS Comments: | Software for Feature Assignments - LipidSearch |
| Ion Mode: | NEGATIVE |
| MS ID: | MS004435 |
| Analysis ID: | AN004688 |
| Instrument Name: | Thermo Q Exactive Orbitrap |
| Instrument Type: | Orbitrap |
| MS Type: | EI |
| MS Comments: | Software for Feature Assignments - El-Maven |
| Ion Mode: | NEGATIVE |
