Rapid Identification of Human-Specific AAV Candidates Using MPS
Despite widespread FDA approval of AAV therapies, discrepancies between preclinical outcomes and human clinical responses, including adverse effects like liver toxicity and immune reactions, pose significant challenges. Utilizing microphysiological systems (MPS), such as organoids and organs-on-chips, enables direct assessment of AAV targeting, toxicity, and immunogenicity in human tissue contexts. This approach aids in pre-screening unsuitable candidates and advancing promising ones to clinical trials, supported by regulatory advancements like the FDA Modernization Act 2.0.
Adeno-associated viral (AAV) vectors dominate gene therapy, boasting eight FDA-approved products across diverse diseases. However, their clinical efficacy remains partially predictable due to mismatches between preclinical predictions and real-world outcomes, notably concerning adverse events including liver toxicity, immune responses, and tissue specificity. Microphysiological systems (MPS), encompassing organoids and chips mimicking organs, present a robust solution by offering human-relevant contexts for evaluating AAV vectors regarding tropism, safety, and efficacy. This methodology aligns with emerging methodologies recognized by regulatory bodies such as the FDA Modernization Act 2.0 and NIH's ORIVA, fostering the integration of human-based models in biomedical research. This review encapsulates recent advancements in MPS application for AAV assessment, delineates existing limitations, and proposes a strategic framework for MPS integration into AAV development pipelines. Ultimately, MPS functions as a critical "human-relevant filter" to prioritize vectors most likely to succeed clinically, ensuring only the safest and most efficacious candidates proceed to patient trials.
Reduces clinical failure risks and accelerates novel drug development