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Inherited diseases of the lung such as Surfactant Protein deficiencies are disorders that typically present shortly after birth, resulting in alveolar collapse and respiratory distress in neonates. The prognosis can be poor and in many cases the disorder is fatal, with affected babies dying shortly after delivery. Furthermore, due to the lack of donor organs, and the unstable state of the disease, lung transplantation is rarely attempted in such young children. Progress in developing treatments has been slow as the majority of such diseases are very rare, with many causative mutations and disparate mechanisms of action.

We propose to apply gene therapy and gene editing technologies to repair the mutant genes in lung cells shortly after birth. The full correction of such disorders will be technically very challenging, but we hypothesise that even partial correction may have a significant effect on patient outcome, for example by extending the window in which lung transplantation could be offered. We have experience of the design, production and use of two gene delivery technologies for the treatment of lung diseases: viral vectors based on Lentivirus (LV) and Adeno-Associated Virus (AAV). In order to treat cystic fibrosis, a more common lung disorder, we have developed a highly potent, third-generation, self-inactivating simian immunodeficiency viral vector. The natural viral envelope protein has been replaced with the F & HN proteins from Sendai virus – a practice known as pseudotyping – to direct highly efficient gene delivery to a range of lung cell types. Recombinant AAV is available in a large number of serotypes that offer highly specific cell targeting. This project will exploit these lung gene delivery vectors in combination with cell-specific promoters, to direct long-lasting transgene expression in target cells. The vectors will be evaluated for the potential to reverse disease features in primary human lung cell cultures and mouse models for the treatment of lung disorders.

Training Opportunities

Training Opportunities: The project will be based in the Gene Medicine Research Group in the John Radcliffe Hospital. The group is expert in the development of gene therapy for lung diseases, and has experience in conducting clinical gene therapy trials and vector manufacturing, exposing students to all aspects of translational research. The student will receive training in techniques such as: molecular biology, gene editing, 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.

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. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.

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.

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 support the careers of female students and staff.

Publications

1

Sumner-Jones SG, Davies LA, Varathalingam A, Gill DR, Hyde SC. 2006. Long-term persistence of gene expression from adeno-associated virus serotype 5 in the mouse airways.

Gene Therapy,  13 (24), pp. 1703-13.

http://www.ncbi.nlm.nih.gov/pubmed/16855618
2

Griesenbach U, Inoue M, Meng C, Farley R, Chan M, Newman NK, Brum A, You J, Kerton A, Shoemark A, Boyd AC, Davies JC, Higgins TE, Gill DR, Hyde SC, Innes JA, Porteous DJ, Hasegawa M, Alton EW. 2012. Assessment of F/HN-pseudotyped lentivirus as a clinically relevant vector for lung gene therapy.

Am. J. Respir. Crit. Care Med.,  186 (9), pp. 846-56. http://www.ncbi.nlm.nih.gov/pubmed/22955314
3

Gill DR, Hyde SC. 2014. Delivery of genes into the CF airway.

Thorax,  69 (10), pp. 962-4.

http://www.ncbi.nlm.nih.gov/pubmed/25015239
4

Alton EW, Armstrong DK, Ashby D, Bayfield KJ, Bilton D, Bloomfield EV, Boyd AC, Brand J, Buchan R, Calcedo R, Carvelli P, Chan M, Cheng SH, Collie DD, Cunningham S, Davidson HE, Davies G, Davies JC, Davies LA, Dewar MH, Doherty A, Donovan J, Dwyer NS, Elgmati HI, Featherstone RF, Gavino J, Gea-Sorli S, Geddes DM, Gibson JS, Gill DR, Greening AP, Griesenbach U, Hansell DM, Harman K, Higgins TE, Hodges SL, Hyde SC, Hyndman L, Innes JA, Jacob J, Jones N, Keogh BF, Limberis MP, Lloyd-Evans P, Maclean AW, Manvell MC, McCormick D, McGovern M, McLachlan G, Meng C, Montero MA, Milligan H, Moyce LJ, Murray GD, Nicholson AG, Osadolor T, Parra-Leiton J, Porteous DJ, Pringle IA, Punch EK, Pytel KM, Quittner AL, Rivellini G, Saunders CJ, Scheule RK, Sheard S, Simmonds NJ, Smith K, Smith SN, Soussi N, Soussi S, Spearing EJ, Stevenson BJ, Sumner-Jones SG, Turkkila M, Ureta RP, Waller MD, Wasowicz MY, Wilson JM, Wolstenholme-Hogg P, UK Cystic Fibrosis Gene Therapy Consortium. 2015. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial.

Lancet Respir Med,  3 (9), pp. 684-91.

http://www.ncbi.nlm.nih.gov/pubmed/26149841
5

Alton EW, Beekman JM, Boyd AC, Brand J, Carlon MS, Connolly MM, Chan M, Conlon S, Davidson HE, Davies JC, Davies LA, Dekkers JF, Doherty A, Gea-Sorli S, Gill DR, Griesenbach U, Hasegawa M, Higgins TE, Hironaka T, Hyndman L, McLachlan G, Inoue M, Hyde SC, Innes JA, Maher TM, Moran C, Meng C, Paul-Smith MC, Pringle IA, Pytel KM, Rodriguez-Martinez A, Schmidt AC, Stevenson BJ, Sumner-Jones SG, Toshner R, Tsugumine S, Wasowicz MW, Zhu J.

2017. Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis.

Thorax, Feb;72(2):137-147. 

Research Themes, Tools and Technologies

Supervisors

Key Dates for October 2018 Entry

Application deadline:  12 noon GMT on Monday 8 January 2018

Interviews for shortlisted candidates: Week commencing Monday 22 January 

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How to apply

To apply for a place on the DPhil in Medical Sciences you will need to submit an application using the online application form.

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