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MRC Industrial CASE Studentship: Development of Lentiviral vectors pseudotyped for efficient lung gene transfer

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  • Full or part time
    Dr Gill
  • Application Deadline
    No more applications being accepted

Project Description

Gene therapy, the treatment of inherited or acquired diseases by the delivery of nucleic acid molecules, is a maturing field offering transformational therapeutic strategies for a range of human disorders. The Oxford University Gene Medicine Group is interested in targeting lung disorders and has developed a non-viral (plasmid/liposome) formulation for aerosol delivery to the lungs of patients with Cystic Fibrosis (CF) lung disease (1). Recently the results of their Phase 2b clinical trial were published demonstrating improved lung function in CF patients. Oxford BioMedica (OXB), an Oxford-based company, is developing viral gene therapy vectors for a range of disorders of the eye, brain and immune system (2, 3). Both groups have considerable experience in the use of recombinant lentivirus for gene therapy, including vector manufacturing and clinical trials.

This collaborative project will utilise the expertise of both groups to develop a novel recombinant lentivirus designed to target the lungs. Commonly used lentiviral vectors result in poor lung targeting due to a lack of suitable receptors in the airways. One way to improve lung targeting efficiency is to pseudotype the lentiviral vector with envelope proteins from viruses that have a natural tropism for lung cells. This approach has already been shown to be feasible (4) and this project will exploit this approach focusing on envelopes based on influenza virus. The project will involve identification of an improved influenza HA protein sequence that infects both animal and human airways, so that results generated in animal models will be relevant to the human lung. The new HA pseudotype will be evaluated in comparison with existing pseudotypes in a range of human and animal respiratory models using in vivo bioluminescence lung imaging. Green Fluorescent Protein and lung cell marker antibodies will identify and quantify the lung cell types transduced indicating the respiratory diseases that can be targeted. Scalable, cGMP-compliant production of highly concentrated and purified lentivrus vector will be required for in vivo testing and subsequent translation to clinical studies. The combined expertise of the academic and industrial partners will optimise vector efficiency and maximise vector productivity to progress the novel pseudotyped Lentivirus through pre-clinical study for lead candidate selection.

Students on Industrial CASE Studentships carry out their research with co-supervision from RDM and an industrial partner. This gives students the opportunity to experience both an academic and an industrial research environment during their DPhil. Students will spend a minimum of 3 months working at the premises of the industrial partner during their 4-year project.

This collaborative project will afford a unique opportunity for the student to be exposed to excellent academic and industrial research environments. The successful candidate will:
- develop extensive molecular biology and cell culture skills to design, construct and test new gene therapy vectors.
- undertake Oxford University animal research training to secure a Personal Home Office licence.
- become expert in pulmonary delivery and in vivo evaluation of gene expression through imaging and quantitative gene expression assays.
- be exposed to all aspects of translational research for evaluation and development of therapeutics.

The Oxford BioMedica Research Group is working at the cutting edge of vector design and cell-line engineering, using automation and robotics to gain an economy of scale for high-throughput screening. The successful student will be able to spend time at Oxford BioMedica being exposed to lentiviral vector-based product development, non-clinical study design, GMP manufacture, and clinical trial design and implementation.

Supervision at Oxford BioMedica will be provided by Dr Kyri Mitrophanos and Dr Peter Jones.

Funding Notes

This project is directly funded through an MRC Industrial CASE Studentship. For UK residents, funding covers all fees, a stipend of at least £16,057 per year, travel to/from the premises of the industrial partner, expenses incurred by the student while working at the premises of the industrial partner and a contribution towards conference attendance. For other EU citizens, funding covers fees, travel and additional expenses but no stipend is provided. Note, if you fall outside these categories, funding would be subject to approval by the funding body.

References

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.

PALFI S, GURRUCHAGA JM, RALPH GS, LEPETIT H, LAVISSE S, BUTTERY PC, WATTS C, MISKIN J, KELLEHER M, DEELEY S, IWAMURO H, LEFAUCHEUR JP, THIRIEZ C, FENELON G, LUCAS C, BRUGIÈRES P, GABRIEL I, ABHAY K, DROUOT X, TANI N, KAS A, GHALEH B, LE CORVOISIER P, DOLPHIN P, BREEN DP, MASON S, GUZMAN NV, MAZARAKIS ND, RADCLIFFE PA, HARROP R, KINGSMAN SM, RASCOL O, NAYLOR S, BARKER RA, HANTRAYE P, REMY P, CESARO P, MITROPHANOUS KA. 2014. Long-term safety and tolerability of ProSavin, a lentiviral vector-based gene therapy for Parkinson's disease: a dose escalation, open-label, phase 1/2 trial. Lancet, 383 (9923), pp. 1138-46.

BINLEY K, WIDDOWSON P, LOADER J, KELLEHER M, IQBALL S, FERRIGE G, DE BELIN J, CARLUCCI M, ANGELL-MANNING D, HURST F, ELLIS S, MISKIN J, FERNANDES A, WONG P, ALLIKMETS R, BERGSTROM C, AABERG T, YAN J, KONG J, GOURAS P, PREFONTAINE A, VEZINA M, BUSSIERES M, NAYLOR S, MITROPHANOUS KA. 2013. Transduction of photoreceptors with equine infectious anemia virus lentiviral vectors: safety and biodistribution of StarGen for Stargardt disease. Invest. Ophthalmol. Vis. Sci., 54 (6), pp. 4061-71.

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.

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