Organoids as a platform for personalized antisense oligonucleotide screening: Advancing precision medicine

Organoid technology has transformed precision medicine by enabling patient-specific 3D models that replicate tissue complexity, facilitating high-throughput antisense oligonucleotide (ASO) therapeutic screening. Patient-derived organoids retain donor-specific genetic and phenotypic profiles, offering physiologically relevant platforms for modeling diseases, such as Duchenne muscular dystrophy (DMD). For example, DMD cardiac organoids rapidly identify dystrophin-restoring ASOs through a 6-week validation pipeline, overcoming limitations of 2D cultures by preserving multicellular interactions. Challenges include expanding tissue representation (e.g., skeletal muscle in DMD), enhancing ASO pharmacokinetic modeling in avascular organoids, and standardizing protocols to minimize variability. Future integration of vascularized or organ-on-chip models, multi-tissue assembloids, and artificial intelligence-driven screening could improve predictive accuracy. Chemically optimized ASOs with reduced off-target effects, combined with clustered regularly interspaced short palindromic repeats-based editing, may synergistically enhance therapeutic precision. As regulatory frameworks adapt to incorporate organoid-based validation, this technology accelerates personalized drug discovery for genetic disorders. Addressing present limitations through bioengineering and standardization will solidify organoids as critical tools for tailoring precision therapies to individual patient needs.