Meta-analysis of preclinical models shows enhanced outcomes for focused ultrasound gene therapy in glioblastoma

INTRODUCTION: Focused ultrasound (FUS) is a noninvasive modality for targeted delivery of therapeutic agents across the blood-brain barrier (BBB). We conducted a systematic review and meta-analysis to evaluate the efficacy of FUS-mediated gene therapy in preclinical orthotopic glioblastoma (GBM) in vivo models. METHODS: PubMed, Embase, Scopus, and Web of Science were searched according with PRISMA guidelines to identify studies reporting FUS-mediated delivery of genetic material in orthotopic GBM animal models. Eligible studies assessed gene delivery or therapeutic efficacy in vivo. Data were extracted on vector type, gene payload, microbubble characteristics, and FUS parameters. Primary outcomes included tumor volume reduction, survival, and gene expression in brain tissue. Random-effects meta-analyses were performed to pool effect sizes. RESULTS: Nine studies met inclusion criteria, including viral, non-viral, nanoparticle, and exosome-based vectors. Delivered genes included therapeutic transgenes (MDA-7/IL-24, HSV-TK, shBirc5, CRISPR/Cas9) and reporter genes (luciferase, GFP). FUS parameters varied (0.65-1 MHz; 120-700 kPa; 1-3 min), as did microbubble formulations. Meta-analysis demonstrated FUS significantly enhanced gene expression in brain tissue (pooled effect size 6.34, 95% CI 2.21-18.18), tumor volume reduction (pooled effect size 4.03, 95% CI 1.46-11.12), and survival (HR 1.33, 95% CI 1.13-1.56). Heterogeneity was high, reflecting protocol variability. No significant FUS-related adverse effects were reported. CONCLUSION: FUS-mediated gene therapy improved gene delivery, tumor control, and survival in preclinical glioma models. These findings support FUS as a safe and effective strategy to overcome barriers to central nervous system gene therapy. Further studies are needed to standardize parameters and evaluate long-term outcomes before clinical translation.