D.Phil Studentships in the Radcliffe Department of Medicine

We currently the following D.Phil projects available via the Radcliffe Dep of Medicine's Scholars Programme.

Airway Gene Therapy for Cystic Fibrosis

We are focused on developing gene therapies for lung diseases. The monogenic recessive disease Cystic Fibrosis is caused by mutations in the CFTR chloride channel, and we are currently testing our first gene therapy product (Gene med weblink) in the lungs of CF patients delivered to the lungs as a monthly aerosol.

The trial will assess the potential for clinical benefit after 1 year of treatment. One challenge to clinical success is the need to repeatedly administer the gene therapy at frequent (monthly) intervals, therefore we are developing a more efficient and long-lived viral gene therapy, which can persist for >2years in animal models.

As part of our ongoing gene therapy development, we have generated a novel, clinically-compliant, 'dual function' lentiviral vector capable of expressing not only genes of interest (such as CFTR), but also shRNA molecules that down-regulate other target genes involved in the disease. This combination of efficient gene replacement and down-regulation is a powerful tool to manipulate cell and epithelial physiology. For CF, the dual function vector can express the CFTR chloride channel and also down-regulate the epithelial sodium channel ENaC. Dual therapy to rebalance the levels of both chloride and sodium ions in the lung should be more efficient than treatments targeting only one of these factors. Ultimately this will increase the volume of the airway surface liquid (defective in the CF lung) required to sufficiently rehydrate and protect the lung surface from bacterial infection.

These vectors will be tested in ex vivo models of lung epithelia developed from human primary airway cells and in vivo models of the CF lung. In addition we have the potential to introduce additional sequences to reduce lung inflammation, an additional problem in the diseased CF lung. The fine-tuning of expression of these sequences in airway cells could ameliorate the multi-factorial problems of the CF lung, and could be extended to treat other chronic lung diseases.

Antibody Gene Transfer To The Lung To Prevent Emerging Pulmonary Infections ^Top

Influenza infections cause seasonal epidemics that result in excess of 500,000 deaths worldwide per year. The response of humans to either traditional influenza vaccines or natural infection is limited – providing protection only against closely related viral subtypes. Seasonal vaccines are continually updated in an attempt to keep pace with viral evolution, but this approach provides insufficient protection against novel influenza strains that periodically emerge to cause pandemics. This problem is confounded by the observation that vaccine development lead-time is too slow to support mass vaccination in response to an emerging pandemic.

Recently, however, it has become possible to isolate high-affinity human monoclonal antibodies against highly conserved regions of the influenza HA protein, with the highly desirable ability to neutralise a diverse range of influenza strains.

The Gene Medicine Research Group has experience in gene delivery platforms that direct efficient lung gene therapy. This project aims to combine our clinical gene delivery expertise with the ability to express broadly neutralising anti-influenza antibodies.

We will utilise our leading viral formulation - a novel, patent protected, third-generation, self-inactivating simian immunodeficiency virus (SIV), which is currently in pre-clinical development. Following construction of lentiviral vectors, the pharmacokinetics of antibody expression will be characterised in vivo and the efficacy of viral protection in models of influenza infection evaluated.

It is anticipated that this approach could be applied to combat chronic lung infections such as Pseudomonas colonisation in primary ciliary dyskinesia; and other acute lung infections such as seasonal RSV, and infections arising from newly emerging respiratory pathogens such as SARS and MERS-CoV.


Airway Gene Transfer To Create Lung Protein Factories ^Top

Protein based therapeutics, once a rarely used subset of medical treatments, are now widely adopted with over 130 different proteins/peptides approved for clinical use. Hormone and enzyme replacement therapies have had dramatic clinical impact in chronic diseases such as diabetes and the lysosomal storage disorders (LSDs) Pompe and Gauchers disease.

However these therapies can be associated with high treatment burdens (e.g. multiple daily injections) and extremely high treatment costs (e.g. $200-700K per year for LSDs). Instead, we hypothesise that a single delivery of an efficient lung gene transfer vector to the respiratory epithelium can generate a lung “protein factory”; capable of secreting therapeutic proteins into the systemic circulation to provide an increased quality of life and a decreased treatment cost for a range of endocrine diseases and inborn errors of metabolism.

Our preferred lung gene delivery vector is a novel, patent protected, third-generation, self-inactivating simian immunodeficiency virus (SIV) in which the envelope proteins have been replaced with the F & HN proteins from Sendai virus to increase airway cell targeting. Following delivery to the lung and/or nasal epithelium, the vector directs abundant expression of transgenes for the lifetime of experimental animals.

It has previously been shown that gene transfer to the murine, ferret and sheep lungs results in abundant secretion into the circulation. This project will utilise our SIV gene transfer platform to understand and manipulate the factors required for effective expression and secretion of soluble reporter proteins into the systemic circulation.

This information could then be used to develop Lentiviral vectors for a variety of disease-specific applications including expression of: Factor VIII for haemophilia A; and alpha-galactosidase, alpha-glucosidase or beta-glucocerebrosidase for LSDs.  Metabolic, haemostatic, muscle and cardiorespiratory function will be evaluated in human cell culture and knockout mouse models.


Development of Gene Therapy for Lung Disorders^Top

Inherited diseases of the lung such as Primary Ciliary Dyskinesia (PCD), Pulmonary Alveolar Proteinosis (PAP) and Surfactant Protein B (SPB) deficiency (SPBD) are disorders that typically present shortly after childbirth. The prognosis for such disorders is poor, with no effective treatments. In some cases such as SPBD the disorder is life-threatening, with affected children dying shortly after childbirth.

There has been little real interest in developing treatments within the pharmaceutical sector, probably due to the low frequency of incidence (1:20,000-50,000 live births) and the disparate mechanisms: PCD is caused by a defective lung membrane protein; PAP is the result of defective alveolar macrophage maturation, and SPBD is due to defective SPB secretion by type II pneumocytes. Rather than focus on multiple disease-specific drug development programmes, we are developing a single platform gene transfer system capable of treating all such lung disorders using gene therapy.

In order to treat cystic fibrosis (CF) a more common lung disorder we have developed a highly potent, novel, patent protected, third-generation, self-inactivating simian immunodeficiency virus in which the envelope proteins have been replaced with the F & HN proteins from Sendai virus and transgene expression is under the control of a CpG-free enhancer/promoter. The vector system has been developed with clinical use in mind and is currently entering late-stage toxicology studies prior to clinical trials.

We have demonstrated previously that the vector directs abundant expression of transgenes within the lung for the lifetime of experimental animals. We will generate lentiviral expression vectors suitable for the treatment of PCD, PAP and SPB and evaluate reversal of disease features in primary human lung cell cultures generated both directly from patients and via iPSC technology and in knockout mouse models.


Training Oppotunities^Top

The project will be based in the Gene Medicine Research Group in the John Radcliffe Hospital [www.genemedresearch.ox.ac.uk]. The group are experts in the development of gene therapy for lung diseases, and has experience in conducting clinical gene therapy trials, exposing students to all aspects of translational research.

The student will receive training in techniques such as: molecular biology, cell culture, microscopy & imaging, protein characterisation along with virus production/purification and functional evaluation, PCR, FACS, Western blotting, immunocytochemistry, ELISA, Quantitative (RT)-PCR, lentivirus production, & Tangential Flow Filtration (TFF) methods.

The student is encouraged to attend the weekly Methods & Techniques training course based in the nearby Weatherall Institute of Molecular Medicine, as well as internal and guest speaker programmes. All students are expected to participate in training workshops within Oxford University Medical Sciences Division focusing on generic and transferable skills for career progression, including scientific writing and presentation skills, ethics, intellectual property, statistics, etc.


How to Apply^Top

Details on how to apply can be found here, on our departmental website.

Further information for applicants



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