Summary of Study ST002857

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	ST002857
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 CSF
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 Denver
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
Submit Date	2023-09-08
Raw Data Available	Yes
Raw Data File Type(s)	mzXML
Analysis Type Detail	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:	SU002969
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	TimeGroup
SA308802	DS1-123-072	FU1
SA308803	DS1-123-035	FU1
SA308804	DS1-123-032	FU1
SA308805	DS1-123-070	FU1
SA308806	DS1-123-125	FU1
SA308807	DS1-123-057	FU1
SA308808	DS1-123-046	FU1
SA308809	DS1-123-139	FU1
SA308810	DS1-123-134	FU1
SA308811	DS1-123-103	FU1
SA308812	DS1-123-005	FU1
SA308813	DS1-123-100	FU1
SA308814	DS1-123-146	FU1
SA308815	DS1-123-094	FU1
SA308816	DS1-123-124	FU12
SA308817	DS1-123-136	FU12
SA308818	DS1-123-058	FU12
SA308819	DS1-123-111	FU12
SA308820	DS1-123-093	FU12
SA308821	DS1-123-073	FU12
SA308822	DS1-123-063	FU12
SA308823	DS1-123-031	FU12
SA308824	DS1-123-027	FU12
SA308825	DS1-123-148	FU12
SA308826	DS1-123-083	FU6
SA308827	DS1-123-127	FU6
SA308828	DS1-123-105	FU6
SA308829	DS1-123-018	FU6
SA308830	DS1-123-011	FU6
SA308831	DS1-123-080	FU6
SA308832	DS1-123-037	FU6
SA308833	DS1-123-043	FU6
SA308834	DS1-123-007	REND
SA308835	DS1-123-123	REND
SA308836	DS1-123-117	REND
SA308837	DS1-123-116	REND
SA308838	DS1-123-102	REND
SA308839	DS1-123-106	REND
SA308840	DS1-123-145	REND
SA308841	DS1-123-028	REND
SA308842	DS1-123-071	REND
SA308843	DS1-123-042	REND
SA308844	DS1-123-133	REND
SA308845	DS1-123-087	REND
SA308846	DS1-123-021	REND
SA308847	DS1-123-131	REND
SA308848	DS1-123-050	REND
SA308849	DS1-123-130	START
SA308850	DS1-123-142	START
SA308851	DS1-123-081	START
SA308852	DS1-123-025	START
SA308853	DS1-123-039	START
SA308854	DS1-123-015	START
SA308855	DS1-123-014	START
SA308856	DS1-123-003	START
SA308857	DS1-123-051	START
SA308858	DS1-123-076	START
SA308859	DS1-123-109	START
SA308860	DS1-123-099	START
SA308861	DS1-123-085	START
SA308862	DS1-123-001	START
SA308863	DS1-123-114	START

Showing results 1 to 62 of 62

Showing results 1 to 62 of 62

Collection:

Collection ID:	CO002962
Collection Summary:	lumbar puncture for serum and CSF collection (stored at -80°C)
Sample Type:	CSF

Treatment:

Treatment ID:	TR002978
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);

Treatment ID:

TR002978

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:	SP002975
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).

Sampleprep ID:

SP002975

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	AN004679	AN004680	AN004681	AN004682	AN004683
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	ESI
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	NEGATIVE	POSITIVE	NEGATIVE
Units	Peak area	Peak area	Peak area	Peak area	Peak area

Chromatography:

Chromatography ID:	CH003521
Chromatography Summary:	Metabolomics Positive Mode
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:	CH003522
Chromatography Summary:	Metabolomics Negative Mode
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:	CH003523
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-.45ml/min
Solvent A:	75:25 H2O:ACN 5mM NH4OAc
Solvent B:	90:10 iPrOH:ACN 5mM NH4OAc
Chromatography Type:	Reversed phase

Chromatography ID:	CH003524
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-.4ml/min
Solvent A:	75:25 H2O:ACN 5mM NH4OAc
Solvent B:	90:10 iPrOH:ACN 5mM NH4OAc
Chromatography Type:	Reversed phase

Chromatography ID:	CH003525
Chromatography Summary:	Oxylipin Method
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:	.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:	MS004426
Analysis ID:	AN004679
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:	MS004427
Analysis ID:	AN004680
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:	MS004428
Analysis ID:	AN004681
Instrument Name:	Thermo Q Exactive Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Software for Feature Assignments - Lipidsearch
Ion Mode:	NEGATIVE

MS ID:	MS004429
Analysis ID:	AN004682
Instrument Name:	Thermo Q Exactive Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Software for Feature Assignments - Lipidsearch
Ion Mode:	POSITIVE

MS ID:	MS004430
Analysis ID:	AN004683
Instrument Name:	Thermo Q Exactive Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Software for Feature Assignments - El-Maven
Ion Mode:	NEGATIVE