REGENT
Research type
Research Study
Full title
REGENT (RETiNal GENE ThERapy immunNE REspoNsE) – a clinical research study on the incidence and severity of gene therapy-associated uveitis [GTAU] and associated predictive factors
IRAS ID
314983
Contact name
M. Dominik Fischer
Contact email
Sponsor organisation
Oxford University Hospitals NHS Foundation Trust
Duration of Study in the UK
3 years, 0 months, 1 days
Research summary
Viral infections and antiviral immune responses can damage the eye. The ocular immune privilege is a clever way of nature to limit such damage. However, this privilege is potentially compromised by disease processes and surgical trauma in the case of retinal gene therapy (GT). Surgical delivery of adeno-associated virus (AAV) potentially induces GT-associated uveitis (GTAU) after ocular delivery in patients with pre-existing retinal disease. Progress has been made addressing the innate immune response to AAV, but not regarding adaptive immunity: Anti-AAV antibody titers do not correlate or predict GTAU risk or severity; but adaptive immune cells have the potential to limit therapeutic effects of GT (50% therapeutic effect is lost within the first year via immune-mediated clearance of treated cells in liver). Immune-mediated clearance of treated cells in the eye could explain an observed decline in functional benefit following ocular GT. It is therefore crucial to better understand the risks, consequences, and best management of GTAU. This project will gather vitreous and bloods samples taken from patients exposed to therapeutic AAV. Hypothesis driven analysis of these samples will help to 1) test, whether subretinal gene therapy leads to increase in ocular and systemic inflammation markers beyond the expected postsurgical recovery phase; 2) identify biomarkers of cellular adaptive immunity (e.g. CD4/CD8 ratio) that can predict risk and severity of GTAU; and 3) identify biomarkers of adaptive immunity that can be used to quantify and monitor GTAU severity. Closing these knowledge gaps will provide a unique opportunity to identifying strategies of targeted intervention limiting potentially detrimental effects of an immune response against therapeutic virus used for gene therapy.
REC name
North West - Greater Manchester Central Research Ethics Committee
REC reference
23/NW/0030
Date of REC Opinion
30 Mar 2023
REC opinion
Further Information Favourable Opinion