Oral Presentation ASSCR, AGCTS, ISCT ANZ and Friends Joint Scientific Conference 2019

High-throughput selection of novel AAV capsids in a murine xenograft liver model: towards next generation of human liver-tropic AAV variants (#22)

Renina G.O. Navarro 1 , Marti Cabanes-Creus 1 , Sophia H.Y. Liao 1 , Cindy Zhu 2 , Grober Baltazar 1 , Kyle Chiang 3 , Matthias Hebben 3 , Ian Alexander 2 4 , Leszek Lisowski 1 5
  1. Translational Vectorology Group, Children's Medical Research Institute, Westmead, New South Wales, Australia
  2. Gene Therapy Research Unit, Children's Medical Research Institute, Westmead, New South Wales, Australia
  3. LogicBio Therapeutivcs, Cambridge, MA, United States of America
  4. Discipline of Child and Adolescent Health, Sydney Medical School, Faculty of of Medicine and Heath, The University of Sydney, Westmead, New South Wales, Australia
  5. Military Institute of Hygiene and Epidemiology, The Biological Threats Identification and Countermeasure Centre, Pulawy, Poland

rAAV vectors are the technological foundation underpinning numerous recent successes in human gene therapy trials, with high-profile examples targeting diseases of the eye, liver and central neuron system. AAV is the only in vivo viral gene delivery tool to achieve regulatory approval by the US FDA or the European Medicines Agency. These successes hinge on continuing progress in the development of AAV-based gene delivery systems, driven primarily by advances in capsid development.

To this end, the Children’s Medical Research Institute (CMRI) and Boston, US-based LogicBio Therapeutics have established a joint program, with the goal to develop the next generation of AAV bioengineered vectors for liver-targeted therapy. This unique combination of academic and industrial expertise has allowed the team to set up a AAV development pipeline, which combines selection of the most functional AAV variants with an early focus on improving manufacturability and immunological profiles.

Here we present the vector selection and validation pipeline, as well as novel AAV variants optimised for highly efficient functional transduction of primary human hepatocytes and high-yield manufacturability. This pipeline includes generation of highly variable AAV capsid libraries based on DNA-shuffling and peptide-display, selection and validation in a biologically-predictive xenograft model of human liver, and evaluation of vector manufacturability and seroreactivity. The pipeline takes advantage of our proprietary selection and evaluation platform which allows to screen capsids based  on the physical (DNA) and functional (RNA) transduction of target cells. We will present functional data for several novel AAV variants that transduce primary human hepatocytes with significantly higher efficiency than the three clinically-tested AAV capsids: AAV2/2, AAV2/8 and bioengineered AAV-LK03. Importantly, the technology developed can be directly applied to perform selection on other target tissues, significantly enhancing the impact of the project and paving the way to the development of next-generation of AAV vectors for clinical applications.

  • Have you presented your abstract at another international meeting?: No