A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?
2014
Background: The development of therapeutics is often characterizedbypromisinganimalresearchthatfailstotranslateintoclinical efficacy; this holds for the development of gene therapy in glioma. We tested the hypothesis that this is because of limitations in the internal and external validity of studies reporting the use of gene therapy in experimental glioma. Method:Wesystematicallyidentifiedstudiestestinggenetherapy in rodent glioma models by searching three online databases. The numberofanimalstreatedandmediansurvivalwereextractedand studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy.Weexploredeffectsofstudydesignand qualityandsearched for evidence of publication bias. Results: We identified 193 publications using gene therapy in experimental glioma, including 6,366 animals. Overall, gene therapy improved median survival by a factor of 1.60 (95% CI 1.53–1.67). Study quality was low and the type of gene therapy didnotaccountfordifferencesinoutcome.Studydesigncharacteristics accounted for a significant proportion of between-study heterogeneity.Weobservedsimilarfindingsinadatasubsetlimitedto the most common gene therapy. Conclusion: As the dysregulation of key molecular pathways is characteristic of gliomas, gene therapy remains a promising treatment for glioma. Nevertheless, we have identified areas for improvement in conduct and reporting of studies, and we provide a basis for sample size calculations. Further work should focus on genes of interest in paradigms recapitulating human disease. This might improve the translation of such therapies into the clinic.
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