How Kidney Organoids Enhance Safety in Gene Therapy Trials

Recent advancements in regenerative medicine have introduced human stem cell-derived kidney organoids as promising tools for assessing the safety of gene therapies. Researchers at Massachusetts General Hospital conducted a groundbreaking study, published in Signal Transduction and Targeted Therapy, to explore how these lab-grown mini kidneys can identify hidden risks associated with adeno-associated virus (AAV) vectors used in gene editing.

Traditional preclinical models, primarily animal studies, often fall short in predicting human-specific responses, leading to unforeseen toxicities during clinical trials. This has resulted in severe adverse effects and even patient deaths in some gene therapy trials, including those for Duchenne muscular dystrophy. Recognizing this gap, the research team utilized kidney organoids to evaluate the cellular and molecular impacts of AAV2, a common vector in gene therapy.

The findings revealed that AAV2 can provoke detrimental responses in kidney cells, such as inflammation, DNA damage, fibrosis, and cellular aging, all occurring via the NFκB signaling pathway, even when no gene editing is performed. Notably, the study also demonstrated that the use of bardoxolone methyl, a drug that inhibits NFκB, effectively mitigated these toxic effects without hindering the gene delivery process.

This innovative approach highlights the potential of organoids as human-specific preclinical models capable of detecting adverse effects earlier in the development process. Implementing such systems can improve the safety profile of gene therapies, reducing the likelihood of unexpected side effects when treatments move into clinical phases.

The research team, led by Dr. Ryuji Morizane, aims to further refine organoid technology by introducing vascular structures and more mature cell types to better mimic in vivo conditions. Expanding this methodology to other organ systems and AAV variants could revolutionize the landscape of gene therapy development, making treatments safer and more personalized.

Overall, organoid-based testing offers a critical supplement to existing animal models, providing human-relevant insights that can accelerate drug safety evaluations and improve patient outcomes.

Source: https://medicalxpress.com/news/2025-08-qa-organoids-gene-therapy-trials.html