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Receptor identification of AAV capsids purposed for gene therapeutic use

Centenary Institute

  • Cell and Gene Therapy Grants
Chief Investigator/s:
  • Professor John Rasko AO

The adeno-associated virus (AAV) is gaining widespread use in gene therapy due to its ability to safely and efficiently deliver a genetic payload into a broad range of tissues.

In the clinic, AAV has successfully been used to treat patients with the bleeding disorder haemophilia by delivering a good copy of the Factor IX gene to replace a faulty copy in patient livers. Limitations of previous studies have included a failure to achieve a sustained therapeutic dose and recognition of the AAV particle by the host immune system.

While these problems have been addressed by designing custom AAVs, a tremendous opportunity still remains to further boost therapeutic efficacy by identifying the specific cell entry mechanism or receptor used by AAV’s. We will identify the specific receptors that allow entry of two liver-specific AAVs, one which is already in clinical use, using biochemical and genetic approaches.

We will identify genetic variants that may affect receptor expression and enable us to screen patients for those who will be better responders. We will then screen a ‘library’ of clinically-approved drugs to boost receptor expression and AAV uptake in liver cells in mice. This study will identify new avenues to enhance therapeutic efficacy in patients undergoing gene therapy.