Therapeutic efficacy of genetically engineered neural stem cells in cerebral ischemia: a systematic review and meta-analysis

TL;DR

This study reviews preclinical research and finds that genetically modified neural stem cells may improve stroke treatment by reducing brain damage and improving recovery.

Contribution

The study provides a systematic review and meta-analysis showing genetically modified neural stem cells are more effective than unmodified cells in stroke therapy.

Findings

Genetically modified NSCs significantly reduced lesion volume compared to unmodified NSCs and controls.

Modified NSCs improved neurological recovery in animal stroke models.

The field lacks standardized protocols and large animal studies, hindering clinical translation.

Abstract

Stroke is one of the most common causes of death and permanent neurological disabilities worldwide yet neuroprotective or regenerative therapies do not exist. Genetically modified neural stem cells (NSC) could help overcome key limitations of naïve or unmodified NSCs and improve therapeutic efficacy. The aim of this systematic review and meta-analysis is to evaluate existing preclinical literature using animal models to compare the therapeutic effects of genetically modified NSCs for stroke compared to naïve NSCs or vehicle control.

Controlled studies investigating genetically modified NSC therapy using animal models of stroke were identified using PUBMED, Scopus and the Chinese National Knowledge Infrastructure (CNKI). Primary outcomes were lesion volume reduction and neurological functional recovery measured via Neurological Severity Score (NSS). Data for meta-analysis were synthesized and expressed as standardised mean difference (SMD) with 95% confidence intervals (CI) using inverse variance and a random effects model. Our secondary outcomes of interest included modified NSC survival, NSC differentiation into neurons, endogenous neural integration, anti-inflammatory effects and migratory capacities. Twenty-nine studies were included for systematic review, and eighteen studies were included for meta-analysis. Genetically modified NSCs significantly reduced lesion volume when compared to both naïve NSCs (SMD 1.07; 95% CI: [0.70, 1.43]; p < 0.00001) and vehicle/injury control (SMD 4.60; 95% CI: [2.69, 6.51]; p < 0.00001), and also significantly improved neurological functional recovery compared to both naïve NSCs (SMD 2.75; 95% CI: [0.34, 5.16]; p = 0.03) and vehicle/injury control (SMD 4.28; 95% CI: [0.64, 7.93]; p = 0.02).

Existing preclinical literature suggests that genetically modified NSCs have the potential to improve therapeutic efficacy of NSCs. However, our systematic review revealed the field lacks uniformity in outcomes measured, an optimised protocol for cell therapy and absence of large animal model studies, all of which pose significant barriers to clinical translation and must be addressed for the field to progress. While we were unable to identify a clear candidate gene, our review highlights the potential for genetically modified NSCs as a future adjunct neuroprotective therapy for stroke and warrants further research in this area.

The online version contains supplementary material available at 10.1186/s12967-025-07603-y.

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