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We are focusing on strategies to deliver therapeutics via in vivo delivery of gene transfer vectors to generate ectopic “protein factories” capable of secreting therapeutic proteins into both the lung lumen and the systemic circulation. These approaches aim to provide an increased quality of life and a decreased treatment cost for a range of lung diseases, endocrine diseases and inborn errors of metabolism. The protein factories are established using conventional gene therapy or applying in vivo gene editing to correct defective loci and enable therapeutic protein expression.

Hyde

About the research 

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 cystic fibrosis, 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 inhalations or injections) and extremely high treatment costs (e.g. $200-700K per year for LSDs).

We achieve efficient liver and muscle gene delivery using recombinant adeno-associated virus (rAAV) vectors, while our preferred lung gene delivery approach is a 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 (rSIV.F/HN) to increase airway cell targeting. Delivery of thsese vectors to the appropriate organs results in abundant and long-lived expression of transgenes: for example, therapeutic monoclonal antibodies can be expressed for the lifetime of experimental animals. This project will utilise our experience of in vivo gene transfer and/or in vivo gene editing to understand and manipulate the factors required for effective expression and secretion of therapeutic proteins. Outcomes such as metabolic, haemostatic, muscle and cardio-respiratory function will be evaluated in human cell culture and knockout/genome engineered mouse models while preparing to translate promising approaches to early phase clinical studies.

Training Opportunities

Students will be exposed to many aspects of the translation of gene therapy research, including vector design and production, and the development of assays for correction of gene defects. In addition to cell and molecular biology, the student will receive training in gene editing, microscopy & in vivo 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.

Students are encouraged to attend the MRC Weatherall Institute of Molecular Medicine DPhil Course, which takes place in the autumn of their first year. Running over several days, this course helps students to develop basic research and presentation skills, as well as introducing them to a wide-range of scientific techniques and principles, ensuring that students have the opportunity to build a broad-based understanding of differing research methodologies.

Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively
encouraged to take advantage of the training opportunities available to them.

As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Publications

      

Paul-Smith MC, et al (2018). The murine lung as a factory to produce secreted intrapulmonary   and circulatory proteins. Gene Therapy. 2018 Aug;25(5):345-358. https://www.ncbi.nlm.nih.gov/pubmed/30022127

Alton EW, et al (2017).     Preparation for a first-in-man       lentivirus trial in patients with cystic fibrosis.     Thorax, Feb;72(2):137-147.https://www.ncbi.nlm.nih.gov/pubmed/27852956

 

Supervisors