Development of Gene Therapy for Lung Disorders

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 birth. The prognosis for such disorders can be poor and in some cases, such as surfactant deficiencies, the disorder is fatal, with affected children dying shortly after delivery. There has been little real interest in developing treatments within the pharmaceutical sector, probably due to the low frequency of incidence 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 lung gene delivery platform with the potential to treat many lung disorders using gene therapy.

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 facilitating highly efficient gene delivery to a wide range of lung cell types. With appropriate promoter sequences, we observe robust expression within the lung for the lifetime of experimental animals. This project aims to exploit our lentiviral lung gene delivery technology in combination wlth cell-specific promoters to direct long-lasting transgene expression. 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.

The project will be based in the Gene Medicine Research Group in the John Radcliffe Hospital [www.genemedresearch.ox.ac.uk]. The group is expert 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 and statistics.