In a landmark stride toward enhancing gene therapy, scientists from the Children’s Medical Research Institute (CMRI) have unveiled a revolutionary method for evaluating adeno-associated viral vector-based (AAV) gene therapies using whole human liver explants. This pioneering approach, leaded by Dr. Leszek Lisowski, the head of CMRI’s translational vectorology unit and the communicating author of the publication, utilizes an ex situ normothermic perfusion system. Detailed in Nature Communications, this innovation marks a critical step forward in developing clinically predictive model systems, crucial for the advancement of personalized medicine.

This research tackles the inherent complexities of liver-directed gene therapies by testing a suite of fourteen natural and bioengineered AAV vectors directly within human livers, under conditions both with and without neutralizing human sera. The standout performers, AAV-SYD12 and AAV-LK03, demonstrated superior cellular uptake and transgene expression under non-neutralizing conditions.

However, the study also shed light on the challenge posed by anti-AAV neutralizing antibodies, which extensively neutralized vectors of human origin, like those derived from AAV2/AAV3b, highlighting the efficiency of AAV8-derived variants.

Originating from a collaborative effort between CMRI’s translational vectorology research unit and a team at Royal Prince Alfred Hospital, this innovative approach addresses the limitations of traditional preclinical models in replicating human physiological conditions and predicting clinical outcomes. By directly assessing gene therapeutic function in the target organ, this model not only paves the way for more accurate dose estimation and side effect identification but also opens new avenues for the development of liver-focused gene therapies, potentially revolutionizing treatment strategies for various inherited diseases.

Cabanes-Creus, M., Liao, S.H.Y., Gale Navarro, R. et al. Harnessing whole human liver ex situ normothermic perfusion for preclinical AAV vector evaluation. Nat Commun 15, 1876 (2024).
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