Data from: A systematic review and meta-analysis of gene therapy in animal models of cerebral glioma: why did promise not translate to human therapy?

Background: The development of therapeutics is often characterized by promising animal research that fails to translate into clinical 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: We systematically identified studies testing gene therapy in rodent glioma models by searching three online databases. The number of animals treated and median survival were extracted and studies graded using a quality checklist. We calculated median survival ratios and used random effects meta-analysis to estimate efficacy. We explored effects of study design and quality and searched 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 did not account for differences in outcome. Study design characteristics accounted for a significant proportion of between-study heterogeneity. We observed similar findings in a data subset limited to 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.

研究背景：治疗药物的研发往往会出现极具前景的动物实验结果却无法转化为临床疗效的情况，神经胶质瘤（glioma）基因治疗的研发亦未能例外。我们提出假说：这一困境源于报道实验性神经胶质瘤基因疗法相关研究的内部效度与外部效度存在局限。
研究方法：我们通过检索三个在线数据库，系统筛选了在啮齿类（rodent）神经胶质瘤模型中验证基因疗法疗效的相关研究。提取受试动物数量与中位生存期数据，并采用质量检查表对纳入研究进行质量评分。我们计算了中位生存期比值，采用随机效应元分析（meta-analysis）评估治疗疗效，同时探究了研究设计与研究质量对结果的影响，并检索了发表偏倚的相关证据。
研究结果：我们共筛选得到193篇关于实验性神经胶质瘤基因疗法的文献，涉及受试动物共计6366只。整体而言，基因疗法可使受试动物的中位生存期提升1.60倍（95%置信区间CI：1.53~1.67）。纳入研究的整体质量偏低，且基因疗法的类型无法解释研究结局的差异；而研究设计特征则解释了研究间异质性的显著部分。在限定为最常见基因疗法的子数据集分析中，我们得到了一致的研究结果。
研究结论：鉴于关键分子通路失调是神经胶质瘤的典型病理特征，基因疗法仍是神经胶质瘤颇具前景的治疗手段。然而，我们发现当前相关研究在研究实施与报告规范方面仍存在诸多可改进之处，本研究同时为样本量计算提供了参考依据。未来研究应聚焦于能复现人类疾病特征的实验模型中的临床相关基因靶点，此举或可推动此类疗法向临床转化。