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Preclinical Development of a Therapy for Chronic Traumatic Spinal Cord Injury in Rats Using Human Wharton's Jelly Mesenchymal Stromal Cells: Proof of Concept and Regulatory Compliance.

ABSTRACT: (1) Background: the use of Mesenchymal Stromal Cells (MSC) in emerging therapies for spinal cord injury (SCI) hold the potential to improve functional recovery. However, the development of cell-based medicines is challenging and preclinical studies addressing quality, safety and efficacy must be conducted prior to clinical testing; (2) Methods: herein we present (i) the characterization of the quality attributes of MSC from the Wharton's jelly (WJ) of the umbilical cord, (ii) safety of intrathecal infusion in a 3-month subchronic toxicity assessment study, and (iii) efficacy in a rat SCI model by controlled impaction (100 kdynes) after single (day 7 post-injury) and repeated dose of 1 × 10⁶ MSC,WJ (days 7 and 14 post-injury) with 70-day monitoring by electrophysiological testing, motor function assessment and histology evaluation; (3) Results: no toxicity associated to MSC,WJ infusion was observed. Regarding efficacy, recovery of locomotion was promoted at early time points. Persistence of MSC,WJ was detected early after administration (day 2 post-injection) but not at days 14 and 63 post-injection. (4) Conclusions: the safety profile and signs of efficacy substantiate the suitability of the presented data for inclusion in the Investigational Medicinal Product Dossier for further consideration by the competent Regulatory Authority to proceed with clinical trials.

SUBMITTER: Vives J

PROVIDER: S-EPMC9319990 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Preclinical Development of a Therapy for Chronic Traumatic Spinal Cord Injury in Rats Using Human Wharton's Jelly Mesenchymal Stromal Cells: Proof of Concept and Regulatory Compliance.

Vives Joaquim J Hernández Joaquim J Mirabel Clémentine C Puigdomenech-Poch Maria M Romeo-Guitart David D Marmolejo-Martínez-Artesero Sara S Cabrera-Pérez Raquel R Jaramillo Jessica J Kumru Hatice H García-López Joan J Vidal-Samsó Joan J Navarro Xavier X Coll-Bonet Ruth R

Cells 20220708 14

(1) Background: the use of Mesenchymal Stromal Cells (MSC) in emerging therapies for spinal cord injury (SCI) hold the potential to improve functional recovery. However, the development of cell-based medicines is challenging and preclinical studies addressing quality, safety and efficacy must be conducted prior to clinical testing; (2) Methods: herein we present (i) the characterization of the quality attributes of MSC from the Wharton's jelly (WJ) of the umbilical cord, (ii) safety of intrathec ...[more]

PMID: 35883596

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Project description:Background and aimsIntracranial compliance refers to the relationship between a change in intracranial volume and the resultant change in intracranial pressure (ICP). Measurement of compliance is useful in managing cardiovascular and respiratory failure; however, there are no contemporary means to assess intracranial compliance. Knowledge of intracranial compliance could complement ICP and cerebral perfusion pressure (CPP) monitoring in patients with severe traumatic brain injury (TBI) and may enable a proactive approach to ICP management. In this proof-of-concept study, we aimed to capitalize on the physiologic principles of intracranial compliance and vascular reactivity to CO2, and standard-of-care neurocritical care monitoring, to develop a method to assess dynamic intracranial compliance.MethodsContinuous ICP and end-tidal CO2 (ETCO2) data from children with severe TBI were collected after obtaining informed consent in this Institutional Review Board-approved study. An intracranial pressure-PCO2 Compliance Index (PCI) was derived by calculating the moment-to-moment correlation between change in ICP and change in ETCO2. As such, "good" compliance may be reflected by a lack of correlation between time-synched changes in ICP in response to changes in ETCO2, and "poor" compliance may be reflected by a positive correlation between changes in ICP in response to changes in ETCO2.ResultsA total of 978 h of ICP and ETCO2 data were collected and analyzed from eight patients with severe TBI. Demographic and clinical characteristics included patient age 7.1 ± 5.8 years (mean ± SD); 6/8 male; initial Glasgow Coma Scale score 3 [3-7] (median [IQR]); 6/8 had decompressive surgery; 7.1 ± 1.4 ICP monitor days; ICU length of stay (LOS) 16.1 ± 6.8 days; hospital LOS 25.9 ± 8.4 days; and survival 100%. The mean PCI for all patients throughout the monitoring period was 0.18 ± 0.04, where mean ICP was 13.7 ± 2.1 mmHg. In this cohort, PCI was observed to be consistently above 0.18 by 12 h after monitor placement. Percent time spent with PCI thresholds > 0.1, 0.2, and 0.3 were 62% [24], 38% [14], and 23% [15], respectively. The percentage of time spent with an ICP threshold > 20 mmHg was 5.1% [14.6].ConclusionsIndirect assessment of dynamic intracranial compliance in TBI patients using standard-of-care monitoring appears feasible and suggests a prolonged period of derangement out to 5 days post-injury. Further study is ongoing to determine if the PCI-a new physiologic index, complements utility of ICP and/or CPP in guiding management of patients with severe TBI.

Dataset Information

Preclinical Development of a Therapy for Chronic Traumatic Spinal Cord Injury in Rats Using Human Wharton's Jelly Mesenchymal Stromal Cells: Proof of Concept and Regulatory Compliance.

Publications

Preclinical Development of a Therapy for Chronic Traumatic Spinal Cord Injury in Rats Using Human Wharton's Jelly Mesenchymal Stromal Cells: Proof of Concept and Regulatory Compliance.

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