Culture-adapted AAV2 is a viral vector which is used to deliver gene therapy to the liver. However, clinical trials targeting diseases of the liver have had an 'unexpectedly low success rate' using the vector, according to researchers: who have now found that naturally occurring AAVs may be more effective.

The prototypical AAV2 discovered more than 50 years ago provides the serotype on which the field of AAV vectorology and gene therapy is based. The researchers from Australias Childrens Medical Research Institute (CMRI) say the discovery 'will shake the foundations of the field of AAV-based gene therapeutics and will mark the beginning of a new era not only for biomedical research, but most importantly, for millions of patients affected by genetic disorders'.

One area of interest in gene therapy is using AAVs to target the liver, which is involved in genetic disorders such as haemophilia and various enzyme deficiencies.

AAV2 is a viral vector used to deliver gene therapy to the liver, carrying therapeutic DNA to target cells in the body. It binds to a receptor on the target cell. However, the researchers found that while AAV2 binds to the attachment receptors - heparan sulfate proteoglycans (HSPCs) - it does so too tightly.

This means that the vector can get trapped on other cells in the body and not the target liver cells. This reduces the number of vectors that deliver their therapeutic cargo to the liver, diminishing therapeutic efficacy.

The teams of Dr Leszek Lisowski, Head of the Translational Vectorology Research Unit, and Prof Ian Alexander, Head of the Gene Therapy Research Unit, then turned to naturally occurring vectors isolated from liver samples. They found that these which use an as of yet unknown receptor are much more successful at delivering therapies to the liver.

CMRI researchers are now able to make vectors in the lab that use this better receptor, instead of HSPGs, potentially making the next generation of gene therapy targeting the liver 'vastly more successful'.

Theorizing that manufacturing methods could be playing a role, the researcherscompared traditional AAV vectors grown in culture with naturally occurring vectors that they isolated from liver samples. They observed that the cultured vectors rapidly mutated as they replicated in the lab: with these changes making the vectors bind more tightly to molecules called HSPGs on the surface of liver cells, but also impeding their ability to infect humanized liver cells in mice.

In contrast, the naturally occurring vectors infected liver cells more efficiently and bound less tightly to HSPGs, although these effects disappeared when the scientists grew the natural vectors in culture over time.

This really challenges a basic concept in our field that binding strongly to HSPG was essential for AAVs' entry into human cells and suggests that vectors targeting the other receptor used by natural AAVs, of human liver origin, are likely to be more effective for clinical gene therapy applications, said Dr Lisowski. The prototypical AAV2, discovered over 50yrs ago, is the serotype on which the entire field of AAV vectorology and gene therapy is based.

Our study sheds new light and challenges our previous understanding and corrects misconceptions about how the vector binds to the cells.

Researchers at the CMRI can now start to improve on the use of vectors to help children with liver conditions. A better vector can increase safety and improve efficiency, while the increased therapeutic efficacy will mean lower doses are needed and thus reduce the cost of treatment.

The insights on adeno-associated virus receptor binding can potentially be extended to other tissues beyond the liver, add researchers. This makes this a very impactful study which will change the trajectory of AAV-based gene therapies.

Adeno-associated viruses (AAVs) were discovered in the 1960s. The vectorization of AAV2, a human isolate, in 1984 set in motion the development the use of the viral vector in gene therapy.

The liver is a key target for developing more efficient AAV vector delivery, given its direct involvement in a number of genetic and acquired diseases.

Source: Science Translational Medicine, September 9, 2020.DOI: 10.1126/scitranslmed.aba3312

Title: Restoring the natural tropism of AAV2 vectors for human liver

Authors: M. Cabanes-Creus; C.V. Hallwirth; A. Westhaus; B.H. Ng; S.H.Y. Liao; E. Zhu; R.G. Navarro; G. Baltazar; M. Drouyer; S. Scott; G.J. Logan; S.L. Ginn; I.E. Alexander; L. Lisowski at University of Sydney in Westmead, NSW, Australia; C.V. Hallwirth; S. Scott; G.J. Logan; S.L. Ginn; I.E. Alexander at Sydney Children's Hospitals Network in Westmead, NSW, Australia; A. Westhaus; G. Santilli; A.J. Thrasher at University College London in London, UK.

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Researchers explore naturally occurring viral vectors: 'Our study will change the trajectory of AAV-based gene therapies' - BioPharma-Reporter.com