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Bioengineering of next-generation adeno-associated viral vectors

Children's Medical Research Institute

  • Early-Mid Career Fellowship
Date Funded:
  • 17 May, 2021
Chief Investigator/s:
  • Marti Cabanes Creus

Research intent

Development of clinically-superior next-generation vectors for therapeutic applications using a whole human liver explant preclinical model.

What is the issue?

There is no current approved adeno-associated virus (AAV) based, liver-directed gene therapy product. The AAV capsid is the main determinant of vector potency and current generation AAVs are not very efficient at transducing human livers.

Current models of the human liver are based on xenograft murine models and fail to recapitulate the structural organization of the human lobules. The establishment of a predictive preclinical liver model based on a normothermic perfusion system will allow the development of the nextgeneration AAV vectors with improved liver tropism.

This will position NSW as a global leader in AAV bioengineering and therapeutic development of novel liver-directed gene therapies, enhancing academic research and attracting commercial interest from domestic and international pharmaceutical companies. The project outcome – more efficient AAV capsids – will increase efficacy and safety, while reducing the cost of liver-directed gene therapies.

What does the research aim to do and how?

The research first aims to establish and validate a preclinical model of the human liver, taking advantage of a normothermic perfusion system that can maintain a whole organ under physiological conditions for up to five days. This preclinical model will then be used as the bases to perform a Darwinian selection of novel AAV capsid vectors with improved efficiency for the human liver. To do so, a large pool of AAV variants (called a ‘library’) is generated in the laboratory and selected in the preclinical model. The ‘fittest’ vectors are then recovered from human hepatocytes.