Background: Hypoxic-ischemic encephalopathy (HIE) is a devastating condition affecting around 8.5 in 1000 newborns globally. Therapeutic hypothermia (TH) can reduce mortality and, to a limited extent, disability after HIE. Nevertheless, there is a need for new and effective treatment strategies. Cell based treatments using mononuclear cells (MNC), which can be sourced from umbilical cord blood, are currently being investigated. Despite promising preclinical results, there is currently no strong indicator for clinical efficacy of the approach. This analysis aimed to provide potential explanations for this discrepancy.
Methods: A systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) guidelines. Preclinical and clinical studies were retrieved from PubMed, Web of Science, Scopus, and clinicaltrials.gov using a predefined search strategy. A total of 17 preclinical and 7 clinical studies were included. We analyzed overall MNC efficacy in preclinical trials, the methodological quality of preclinical trials and relevant design features in preclinical versus clinical trials.
Results: There was evidence for MNC therapeutic efficacy in preclinical models of HIE. The methodological quality of preclinical studies was not optimal, and statistical design quality was particularly poor. However, methodological quality was above the standard in other fields. There were significant differences in preclinical versus clinical study design including the use of TH as a baseline treatment (only in clinical studies) and much higher MNC doses being applied in preclinical studies.
Conclusions: Based on the analyzed data, it is unlikely that therapeutic effect size is massively overestimated in preclinical studies. It is more plausible that the many design differences between preclinical and clinical trials are responsible for the so far lacking proof of efficacy of MNC treatments in HIE. Additional preclinical and clinical research is required to optimize the application of MNC for experimental HIE treatment.
Keywords: Cell therapy; hypoxic-ischemic encephalopathy; mononuclear cells; translational research; treatment efficacy.