Preclinical Efﬁcacy Failure of Human CNS-Derived Stem Cells for Use in the Pathway Study of Cervical Spinal Cord Injury

Stem Cell Reports, 2017 · DOI: http://dx.doi.org/10.1016/j.stemcr.2016.12.018 · Published: February 14, 2017

Spinal Cord Injury Regenerative Medicine Research Methodology & Design

Simple Explanation

This study investigates the effectiveness of human neural stem cells (HuCNS-SCs) in treating cervical spinal cord injury (SCI) in mice. Two types of HuCNS-SC lines were tested: a research cell line (RCL) and a clinical cell line (CCL) intended for human trials. The RCL showed some promise in improving locomotor function when transplanted shortly after injury. However, the CCL, intended for clinical use, did not show any benefit and, in some cases, appeared to worsen outcomes. These findings raise concerns about how stem cell therapies are developed and tested before being used in human clinical trials, particularly regarding the consistency and reliability of cell lines and the need for thorough preclinical testing.

Study Duration

12 Weeks Post-transplant

Participants

Mice, including Rag2g and Agouti Rag2g(c) hybrid strains

Evidence Level

Not specified

Key Findings

1
The research cell line (HuCNS-SC RCL) showed some improvement in locomotor function when transplanted 9 days post-injury (DPI) in mice with cervical SCI.
2
The clinical cell line (HuCNS-SC CCL), intended for human trials, failed to demonstrate efficacy in the mouse model of cervical SCI, and some data suggested a negative impact on outcomes when transplanted 60 DPI.
3
There were differences in the differentiation potential of the RCL and CCL, with the CCL showing a reduced capacity to differentiate into mature oligodendrocytes in the injured microenvironment.

Research Summary

This study evaluated the efficacy of human neural stem cells (HuCNS-SCs) in a mouse model of cervical spinal cord injury (SCI), comparing a research cell line (RCL) and a clinical cell line (CCL) intended for human trials. While the RCL showed some promise in improving locomotor function, the CCL failed to demonstrate efficacy and, in some instances, appeared to negatively impact outcomes, raising questions about the validity of animal models, cell line comparability, and preclinical testing standards. The authors emphasize the importance of rigorous preclinical testing of clinical cell lines and the need for robust potency/comparability assays to ensure consistency and reliability in stem cell therapies before clinical translation.

Practical Implications

Re-evaluation of Preclinical Testing Standards

The study highlights the need for stricter in vivo preclinical testing of clinical cell lines before human trials, particularly concerning potency and comparability assays.

Improved Cell Line Development

The findings suggest that inconsistencies in cell manufacturing and processing can significantly impact the efficacy of stem cell therapies, emphasizing the need for standardized GMP production.

Informed Consent Considerations

The authors raise concerns about the adequacy of current standards for demonstrating potency and comparability between therapeutic cell lots, which has implications for informed consent during patient enrollment in clinical trials.

Study Limitations

1
Potential variation between cell lines and/or in cell manufacture/processing.
2
Applicability of endpoints in an animal model to the human condition.
3
The CCL cells tested herein may not be representative of the cells used in the Pathway Study.

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