Effects of Intravascular Administration of Mesenchymal Stromal Cells Derived from Wharton's Jelly of the Umbilical Cord on Systemic Immunomodulation and Neuroinflammation After Traumatic Brain Injury.
- Conditions
- Traumatic Brain Injury
- Interventions
- Drug: Mesenchymal Stromal Cells (MSC)Drug: placebo
- Registration Number
- NCT06146062
- Lead Sponsor
- Assistance Publique - Hôpitaux de Paris
- Brief Summary
Traumatic brain injuries (TBI) are one of the leading causes of death and disability worldwide. These patients are burdened by physical, cognitive, and psychosocial deficits, leading to an important economic impact for society. Treatments for TBI patients are limited and none has been shown to provide prolonged and long-term neuroprotective or neurorestorative effects. TBI related disability is linked to the severity of the initial injury but also to the following neuroinflammatory response which may persist long after the initial injury.
Moreover, a growing body of evidence suggests a link between TBI-induced neuro-inflammation and neurodegenerative post traumatic disorders. Consequently, new therapies triggering immunomodulation and promoting neurological recovery are the subject of major research efforts.
In this context, mesenchymal cell-based therapies are currently investigated to treat various neurological disorders due to their ability to modulate neuroinflammation and to promote simultaneous neurogenesis, angiogenesis, and neuroprotection.
Clinical trials using intravenous MSC have been conducted for various pathologies, all these studies showing a good safety profile.
The hypothesis of the study is that intravenous repeated treatment with MSC derived from Wharton's Jelly of the umbilical cord may be associated with a significant decrease of post-TBI neuroinflammation and improvement of neuroclinical status.
The main objective of the study is to evaluate the effect of iterative IV injections of MSC on post-traumatic neuroinflammation measured in corpus callosum by PET-MRI at 6 months in severe brain injured patients unresponsive to simple verbal commands 5 days after sedation discontinuation.
- Detailed Description
Traumatic brain injuries (TBI) are one of the leading causes of death and disability worldwide. These patients are burdened by physical, cognitive, and psychosocial deficits, leading to an important economic impact for society. Treatments for TBI patients are limited and none has been shown to provide prolonged and long-term neuroprotective or neurorestorative effects. TBI related disability is linked to the severity of the initial injury but also to the following neuroinflammatory response which may persist long after the initial injury.
Moreover, a growing body of evidence suggests a link between TBI-induced neuro-inflammation and neurodegenerative post traumatic disorders. Consequently, new therapies triggering immunomodulation and promoting neurological recovery are the subject of major research efforts.
In this context, mesenchymal cell-based therapies are currently investigated to treat various neurological disorders due to their ability to modulate neuroinflammation and to promote simultaneous neurogenesis, angiogenesis, and neuroprotection. Indeed, several experimental studies have reported that human umbilical cord-derived mesenchymal stromal cells (MSC) have the ability to improve neurological outcomes and recovery in cerebral injury animal models, including TBI.
Clinical trials using intravenous MSC have been conducted for various pathologies, all these studies showing a good safety profile. In TBI, small clinical trials using different modalities for administration of mesenchymal cells are available but none about MSC derived from Wharton's Jelly of the umbilical cord.
The hypothesis of the study is that intravenous repeated treatment with MSC derived from Wharton's Jelly of the umbilical cord may be associated with a significant decrease of post-TBI neuroinflammation and improvement of neuroclinical status.
The main objective of the study is to evaluate the effect of iterative IV injections of MSC on post-traumatic neuroinflammation measured in corpus callosum by PET-MRI at 6 months in severe brain injured patients unresponsive to simple verbal commands 5 days after sedation discontinuation.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 68
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Intervention Mesenchymal Stromal Cells (MSC) Final product is a MSC solution at the concentration of 2.10\^6/kg in 150 mL of NaCl 0.9% and human albumin 0.5%, conditioned aseptically and identified for IV administration. 3 injections one week apart. control placebo The placebo will be a solution of NaCl 0.9% 3 injections one week apart.
- Primary Outcome Measures
Name Time Method effect of iterative IV injections of WJ-UC-MSC on post-traumatic neuroinflammation 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in corpus callosum (Region of Interest, ROI) measured by dynamic PET-MRI
- Secondary Outcome Measures
Name Time Method cognitive assessment M12 12 months after the last injection MOCA scale
Neurological clinical Score M6 6 months after the last injection Glasgow Outcome Scale-Extended
radiological markers from PET-MRI_2 6 months after the last injection The mean diffusibility (MD) from DTI acquisition of PET-MRI
Treatment feasibility at the third injection number of treatments administrated to the patient
Neurological clinical Score M12 12 months after the last injection Glasgow Outcome Scale-Extended
cognitive assessment M6 6 months after the last injection MOCA scale
radiological markers from PET-MRI_1 6 months after the last injection The regional fractional anisotropy (FA) from DTI acquisition of PET-MRI
short term Tolerance D10 10 days after the last injection Common Terminology Criteria for Adverse Events
long term Tolerance M6 6 months after the last injection Common Terminology Criteria for Adverse Events
long term Tolerance M12 6 months after the last injection Common Terminology Criteria for Adverse Events
neuroinflammation of pericontusional 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in pericontusional
neuroinflammation of grey matter 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in grey matter
neuroinflammation of white matter 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in white matter
neuroinflammation of frontal area 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in frontal area
neuroinflammation of parietal area 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in parietal area
neuroinflammation of occipital area 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in occipital area
neuroinflammation of hippocampus 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in hippocampus,
neuroinflammation of thalamus 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in thalamus,
neuroinflammation of mesencephalus 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in mesencephalus
neuroinflammation of cerebellum 6 months after the last injection \[18F\]-DPA-714 Standard Uptake Value ratio (SUVr) in cerebellum
Cytokine and chemokine levels in plasma 6 months after the last injection Luminex magnetic beads technology
PBMC profile 6 months after the last injection High-dimensional characterization of immune reprogramming during the treatment by single-cell RNA-sequencing of PBMC.
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 1. 6 months after the last injection H3K27ac
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 2. 6 months after the last injection H3K4me3
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 3. 6 months after the last injection ChIP-seq
Transcriptomics and regulatory epigenomics of circulating monocytes and lymphocytes 4. 6 months after the last injection ATAC-seq
Genome-wide single-nucleotide polymorphism (SNP) genotype. After 1 injection DNA sample
Trial Locations
- Locations (3)
Hôpital National d'Instruction des Armées Percy
🇫🇷Clamart, France
Beaujon Hospital
🇫🇷Clichy, France
Hôpital de la Pitié Salpêtrière - AP-HP
🇫🇷Paris, France