Microphysiological systems to accelerate and de-risk AAV gene therapy development.

Area of Science:

• Biomedical Engineering
• Gene Therapy
• Toxicology

Background:

• Adeno-associated viral (AAV) vectors are crucial for gene therapy, but clinical outcomes are unpredictable.
• Discrepancies between preclinical models and human trials, especially regarding toxicity and tropism, hinder AAV vector development.
• Regulatory bodies increasingly support human-based models for drug development.

Purpose of the Study:

• To review the application of microphysiological systems (MPS) for evaluating AAV vectors.
• To outline the limitations of current MPS technologies in AAV research.
• To propose a framework for integrating MPS into the AAV development pipeline.

Main Methods:

• Review of recent literature on MPS applications for AAV vector evaluation.
• Analysis of MPS capabilities in predicting AAV tropism, safety, and efficacy.
• Discussion of regulatory initiatives promoting New Approach Methodologies (NAMs).

Main Results:

• MPS provide a human-relevant context for assessing AAV vector behavior.
• These systems can help identify potential adverse events like liver toxicity and immune responses.
• MPS facilitate de-risking and accelerating the development of gene therapy candidates.

Conclusions:

• MPS represent a significant advancement in evaluating AAV vectors for gene therapy.
• Integrating MPS can serve as a "human-relevant filter" to select promising AAV candidates.
• Wider adoption of MPS will enhance the safety and efficacy of gene therapies reaching patients.