Regulating Synthetic Biology and Advanced Genetic Interventions: Biosecurity Frameworks, Gene Therapy Oversight, Stem-Cell Manufacturing Risks and Future Policy Directions

Gene editing (CRISPR-Cas9, base and prime editing), viral-vector therapies (adeno-associated virus AAV and lentiviral systems) and engineered stem cell platforms (induced pluripotent stem cells and mesenchymal lines) have transformed disease treatment but also introduced profound biosafety risks, regulatory gaps and biosecurity threats. The current review examines dual-use research of concern (DURC) in synthetic biology, highlighting how artificial intelligence (AI)-assisted design and cloud-based DNA synthesis increase the risk of misuse, as reflected in 2024 DARPA findings on democratised genome engineering. Several significant biohazards have been identified, including immune toxicities such as cytokine release syndrome observed in certain gene and cell therapy trials; viral shedding and recombination, including the rare detection of replication-competent viral particles in some AAV vector studies; off-target genomic rearrangements, such as chromothripsis-like events reported in some CRISPR editing studies; and long-term oncogenic risks from epigenetic dysregulation. Stem-cell manufacturing carries several risks, including oncogenic potential, genetic aberrations and recipient dysfunctions, such as ectopic engraftment, which can disturb immune and metabolic balance. Reviews of global regulations highlight significant gaps and fragmentation: National Institutes of Health recombinant DNA guidelines trail behind the EU’s Advanced Therapy Medicinal Product (ATMP) framework and ISO 20399 standards, with no harmonisation for low- and middle-income countries and an absence of biosurveillance infrastructure. Evidence from recent clinical trials, such as reported vector shedding cases in Luxturna studies, emphasises the need for metabolomics-based risk mapping. Future directions include the establishment of an integrated global biosafety registry for real-time adverse event tracking, DURC oversight supported by AI-based sequence screening, multi-omics risk evaluation, harmonised good manufacturing practice standards and ethical frameworks that address accountability amid rapid technological advances.