Stem Cell and Gene Therapies in Congenital Heart Disease: A Systematic Review.

INTRODUCTION To systematically evaluate the safety, feasibility, and efficacy of stem cell and gene therapies in congenital heart disease (CHD).

Methods

The search included PubMed/MEDLINE, Embase, Scopus, Cochrane Library, and ClinicalTrials.gov databases for human and animal studies published in English from January 2000 through June 2025. Preclinical and clinical studies on stem cell/gene therapy for CHD that reported structural, functional, and safety outcomes were assessed. Due to heterogeneity, data were narratively synthesized.

Results

Of 1, 128 records, 30 studies met the inclusion criteria, comprising 14 clinical studies, 16 preclinical investigations, and an additional 8 ongoing trials. Most clinical studies focused on single-ventricle physiology, especially HLHS. The interventions demonstrated generally reassuring short-term safety profiles, with none reporting malignant changes or cell-related organ toxicities. Efficacy outcomes were inconsistent, as some trials demonstrated improvements in ventricular function parameters with long-term benefits, whereas others showed no functional improvements despite a favorable safety profile. No definitive clinical trials of gene therapy in CHD have yet been completed.

Discussion

Although the number of clinical trials is limited, the collective findings suggest potential translational applicability of regenerative therapy in the management of congenital heart diseases. The available evidence is limited by small and heterogeneous sample sizes. Future strategies would need to focus on multicenter clinical trials and the application of newer modalities to provide durable responses.

Conclusions

Stem cell therapies for CHD have demonstrated encouraging biologic signals and generally reassuring early safety data. Rigorous multicenter randomized controlled trials with standardized endpoints and long-term follow-up are needed to define their actual therapeutic effectiveness.