Overcoming innate immunity towards genetic therapies in the eye

29/08/2018 to 28/08/2021

A large number of blinding disorders caused by monogenic mutations lead to neuroretinal degeneration with no treatment currently available. Gene therapy carries the potential to counteract this degeneration and Adeno-associated virus (AAV) has become a widely used vector system for gene transfer in the eye. However, independent AAV gene therapy trials reported cases with ocular inflammation and loss of efficacy after initial functional improvements. One explanation for the decline of efficacy might be a host immune response directed against AAV and/or transduced cells. Our own data demonstrate that clinical grade AAV can indeed activate the pathogen-associated pattern recognition (PPR) system in the primate retina and consequently induce an immune response through effector cytokines.

Although AAV biology has been studied quite extensively, the interaction between recombinant AAV and the PPR system in retinal cells is not well understood. As the PPR system and downstream effector cytokines help to stage a concerted immune response, a thorough understanding of these interactions is of critical importance for AAV-mediated gene therapy. This proposal aims to increase the safety and efficacy of future AAV-mediated gene transfer by identifying the key pathways leading to the ocular immune response against AAV and finding ways to modulate those to limit inflammation and ensure long-term therapeutic transgene expression.