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Overcoming immune responses to retinal gene therapy


Faculty of Health Sciences

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Dr D Copland , Prof A Dick No more applications being accepted Funded PhD Project (Students Worldwide)

About the Project

Our research group is a world leader in ocular immunology, combining studies of human disease with experimental animal models to understand fundamental underlying biological mechanisms. We are offering an exciting 3-year PhD studentship for a candidate interested in exploring novel approaches for ocular gene therapy.

Adeno-associated virus (AAV) gene therapy vectors have emerged as an important delivery platform for the treatment of many different types of ocular disease. However, intraocular inflammation and persistent loss of visual acuity are increasingly reported in clinical trials using subretinal or intravitreal AAV administration protocols. Inflammatory responses can directly reduce the efficacy of gene expression, or indirectly by limiting sufficient dose escalation in patients. These findings highlight fundamental limitations which must be resolved for wider ocular application.

The PhD studentship will test the hypothesis that intraocular administration of AAV vectors permanently alters the immune threshold and perturbs the normal homeostatic function of retinal microglia. Using a combination of clinical imaging and FACS, the project will characterize the in vivo temporal dynamics, correlating the timing of transgene expression, microglial activation and infiltration of immune cells. Using an established RNA-Seq protocol, low numbers of FACS-sorted cells obtained at early and late time-points will determine inflammation responsive transcriptional signatures of isolated microglia, subsets of infiltrating lymphocytes, and GFP+ AAV-transduced retinal cells. Finally, the project will assess whether interventions to inhibit cellular infiltration or activation prevent changes in tissue homeostasis to maintain enhanced transgene expression

To do this we have established a mouse model of AAV-mediated ocular inflammation following intravitreal administration of vector expressing GFP transgene. High resolution in vivo imaging shows severe inflammation, and multiparameter flow cytometry (FACS) assessment demonstrates the predominant immune cell infiltrate is comprised of CD3+ T cell subsets. Using the Cx3cr1CreER:R26-tdTomato mouse (a specific microglia reporter expressing tdTomato), clinical and post-mortem imaging demonstrates that retinal microglia are highly activated and increased in number.

The student will join a flourishing ocular immunology and gene therapy group based in the Medical Sciences Building at the University of Bristol. We are the lead centre for Inflammation and Immunotherapeutics within the NIHR Biomedical Research Centre in Ophthalmology at Moorfields Eye Hospital, UCL Institute of Ophthalmology and collaboration with the University of Bristol. Our expertise has extended to develop collaborations with research groups based in USA (National Eye Institute, NIH, Harvard, University of Washington in Seattle) and Zhongshan Ophthalmic Center state laboratories, China. The student will learn a wide range of techniques, including AAV vector generation, flow cytometry, RNA-seq, confocal microscopy, qPCR, and in vivo imaging techniques. The group has an established track record of PhD students and this is one of two positions on offer this year.

The PhD student will be based within the Ophthalmology Research Laboratories at the University of Bristol. The candidate will start in April 2021, directly supervised by a team consisting of Dr Dave Copland, Professor Andrew Dick and Dr Colin Chu, with additional support from Dr Ying Kai Chan (collaborator at University of Harvard).

Candidate requirements:
Applications are sought from high performing individuals who have a 1st or 2.1 higher degree (or equivalent) in a biomedical or related life sciences discipline. Possession of a relevant Masters degree or research experience would be advantageous, but is not expected.

How to apply:
Please make an online application for this project at http://www.bris.ac.uk/pg-howtoapply. Please select Faculty of Health Sciences and Translation Health PhD on the Programme Choice page. You will be prompted to enter details of the studentship in the Funding and Research Details sections of the form.

For general enquiries linked to the online application process, please email [Email Address Removed]

Further information:
For informal enquiries or further information about this PhD project, please contact Dr Dave Copland ([Email Address Removed]).

Closing Date: 5pm, 26th February


Funding Notes

The studentship is funded by the National Eye Research Centre at standard rates (Stipend of £15,2845 for 20/21) and covers the cost of tuition fees at the rate of home/EU students. International/EU applicants may apply if they can fund the difference in fees which is currently £18,835 per year. The studentship also includes a research consumables allowance. Standard University of Bristol eligibility criteria apply.
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