Fully-funded PhD scholarships available with world-leaders in vectorology and gene therapy. Help develop new treatments and cures. Find out more below. 

Development of a universal gene therapy approach using CRISPR-based genome editing technology to treat paediatric liver disease.

This PhD project aims to develop a universal genome editing platform technology that can be easily adapted to treat urea-cycle disorders and liver disease more broadly. This approach has the advantage of correcting all mutations within the target gene regardless of their type and could, therefore, treat all patients with the same gene therapy vector, ensuring the greatest clinical applicability. In addition, the reagents generated in this project will be configured with the end-in-mind and will be directly translatable without further modification. The project will also identify novel, highly human liver-specific, vectors with the potential to generate intellectual property and commercial interest. Studies will be performed in patient-specific primary human hepatocytes in vivo, the most relevant pre-clinical model for human translation.

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Extending the therapeutic reach and biosafety of AAV-mediated gene transfer vectors to treat human metabolic liver disease: In vivo reactivation of the ornithine transcarbamylase locus in patient cells with skewed X-chromosome inactivation.

The project’s primary objective, developing novel AAV-derived vectors with extended clinical reach for human liver disorders, will be translationally focussed on treating a frontier liver indication. Whilst exciting, treatment of haemophilias by AAV-mediated gene therapy succeeded because gene transfer to a modest proportion of hepatocytes confers therapeutic benefit. The gene transfer efficiency required to treat cell-autonomous indications is far higher, and rAAV technology is presently constrained by the low liver transduction efficiency of clinically deployed capsids. Ornithine transcarbamylase (OTC) deficiency is one such condition that demands the highest-efficiency liver-targeting technology for a clinically corrective intervention. Accordingly, we aim to employ our novel vectors to deliver locus-specific epigenetic engineering payloads to reactivate the wildtype OTC allele in hepatocytes.

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Development, optimisation and manufacturing of novel bespoke technologies for AAV-based gene therapies for neurological disorders

This PhD project aims to develop safe, practical, and affordable gene therapy treatment options focused on patients suffering from debilitating neurological conditions, such as motor neuron disease. Furthermore, this project seeks to improve the manufacturing process of the bioengineered vehicles of gene therapy (termed 'vectors') through the development of novel bespoke manufacturing technologies. The vectors used in this project will be recombinant adeno-associated virus (rAAV), the current vector of choice for gene delivery. The goal of this project is to improve personalised gene therapy treatments to result in readily accessible, affordable, and ready for use in clinical practice. As this project will be primarily based at the Westmead Precinct, the PhD candidate will have access to the cutting-edge technology and expertise present at this world-class facility. Throughout this project, they will be able to master a range of sought-after skills in viral vector design, manipulation of the AAV genome, vector manufacturing, and bioinformatic analysis, providing them with highly sought-after specialised skills.

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Developing a methodological infrastructure for research and quality management of unstable RAAV genome elements in support of clinical vector manufacturing

The DNA cargo of rAAV gene delivery vectors begins and ends with non-linear sequences called inverted terminal repeats (ITRs). These fascinating genome elements are central to the biology of the rAAV vector system – particularly in the process of packaging viral capsids with non-viral DNA sequences of interest. A problem faced in rAAV research is the inability to consistently replicate ITR sequences due to their odd structure and high GC content. Addressing this problem will require methods to analyse and profile DNA samples containing intact and misreplicated ITR elements. The aim of this PhD project will be to develop these methods using an array of available chromatographic, electrophoretic and mass spectrometric technologies. This research problem and its eventual solution are grounded in an engaging array of techniques and subject matter from rAAV vectorology, gene therapy, molecular biology, biometrology, analytical biochemistry and nucleic acids research.

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