Hyde Group - Airway Gene Therapy - Engineering Lentiviral Vectors for Lung Cell-Specific Targeting
- Stephen Hyde
ABOUT THE RESEARCH
The Gene Medicine Research Group is based in Radcliffe Department of Medicine laboratories in the John Radcliffe Hospital and is focused on the development of new gene therapeutics for lung diseases. We use gene therapy and gene editing approaches employing plasmid, lentiviral and AAV platforms for gene delivery in vivo. We are looking for students interested in the translation of new gene therapies to the clinic, including the development of new vectors, and evaluation in animal models of disease.
Serious, monogenic lung diseases such as cystic fibrosis (CF), alpha-1 antitrypsin deficiency (AATD), and surfactant deficiencies caused by mutations in SFTPB or ABCA3 are progressively debilitating disorders that typically cause respiratory distress and are often fatal. We are focused on developing gene transfer and genome editing based treatments for lung disorders with clear unmet clinical need.
The Gene Medicine Research Group has developed a potent, IP -protected, gene delivery platform for the lung. This platform is based on recombinant Simian Immunodeficiency Virus (rSIV) which is pseudotyped with the Sendai Virus Fusion (F) and Haemagglutinin-neuraminidase (HN) glycoproteins (rSIV.F/HN). Our rSIV.F/HN platform has the advantage of integrating a therapeutic gene of interest into the target cells’ genomes – offering potentially life-long curative therapeutic gene expression. This platform has recently licensed by Boehringer Ingelheim for the treatment of individuals with CF.
Improvements in our rSIV.F/HN platform are desirable to improve specific cellular targeting, particularly to treat alveolar disorders such as surfactant deficiencies and idiopathic pulmonary fibrosis. In this project, we propose harnessing the affinity and specificity of cell-type specific antibodies, scFv, and receptor ligands to enhance vector transduction to the desired target cell type. We envision a novel platform to allow modular engineering of the HN component by addition of binding moieties from antibodies, scFv or binding ligands. This will generate novel pseudotypes to drive cell specific targeting with high efficiency. In particular, we aim to engineer novel HN protein hybrids that recognise alveolar type II (ATII) cells, the key progenitor/stem cell type the alveolar region of the lung.
Additional supervision may be provided by Dr Kamran Miah and Dr Thomas Roberts.
The Gene Medicine Group offers various training opportunities to help equip students with the skills and capabilities to become highly competent and independent researchers. We are a well-equipped lab and offer high calibre training in viral vector manufacture (including LV and AAVs), molecular biology (cloning, qRT-PCR, ddPCR, genome editing), immunological techniques (ELISAs, SDS-PAGE, Western Blotting, immunohistochemistry), tissue culturing, and utilisation of relevant lung and disease models, including in vitro using air-liquid interface (ALI) cultures and using transgenic animal models in vivo.
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.
Munday et al., 2022 Mol Ther Methods Clin Dev 26:239. Sendai F/HN pseudotyped lentiviral vector transduces human ciliated and non-ciliated airway cells using alpha 2,3 sialylated receptors.
Lund-Palau et al 2022 Mol Ther Methods Clin Dev 25:382. Correction of a chronic pulmonary disease through lentiviral vector-mediated protein expression.
Du et al., 2022. Frontiers in Immunology, 13:819058. Intranasal Lentiviral Vector Mediated Antibody Delivery Confers Reduction of SARS-CoV-2 Infection in Elderly and Immunocompromised Mice.
Du et al. 2022. Thorax, 77(12):1229-1236. Lung-Directed Antibody Gene Transfer Confers Protection Against SARS-CoV-2 Infection.