Key result
Bioengineered AAV-SYD vectors improve human hepatocyte uptake and transgene expression in liver xenograft mice.
Why the study?
The liver is a key target for AAV-mediated therapeutic gene delivery, driving interest in developing next-generation vectors with enhanced human hepato-tropism.
Do bioengineered AAV-SYD vectors enhance human hepatocyte transduction compared to standard AAV vectors in a liver xenograft mouse model?
Do bioengineered AAV-SYD vectors enhance human hepatocyte transduction compared to standard AAV vectors in a liver xenograft mouse model?
Bioengineered AAV-SYD vectors demonstrate enhanced human hepatocyte tropism, offering potential improvements for liver-directed gene therapies.
Advances options for hepatic gene therapy; leaves open clinical translation from animal models.
Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. Here, we report the bioengineering of a set of next-generation AAV vectors, named AAV-SYDs (where "SYD" stands for Sydney, Australia), with increased human hepato-tropism in a liver xenograft mouse model repopulated with primary human hepatocytes. We followed a two-step process that staggered directed evolution and domain-swapping approaches. Using DNA-family shuffling, we first mapped key AAV capsid regions responsible for efficient human hepatocyte transduction in vivo . Focusing on these regions, we next applied domain-swapping strategies to identify and study key capsid residues that enhance primary human hepatocyte uptake and transgene expression. Our findings underscore the potential of AAV-SYDs as liver gene therapy vectors and provide insights into the mechanism responsible for their enhanced transduction profile.
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Cabanes‐Creus et al. (2021) studied Genetic diseases (liver gene therapy). AAV-SYDs (next-generation AAV vectors) was evaluated on Human hepatocyte transduction in vivo and transgene expression. Bioengineered next-generation AAV vectors (AAV-SYDs) demonstrated increased human hepato-tropism and enhanced primary human hepatocyte uptake and transgene expression in a liver xenograft mouse model.