Retinal Gene Therapy: Bridging the Gap

Abstract

After 50 years of gradual progress, the last decade has seen gene therapy shaping up to be a transformational technology for the treatment of previously untreatable monogenetic disorders. After being set back by several decades, crucial improvements to vector safety have again propelled gene augmentation therapy into translational reality, with monogenetic retinal disorders on the forefront of the development. This dissertation aimed to inform translational efforts towards Germany's first ocular gene therapy trials, which were conducted at the Centre for Ophthalmology in Tübingen. The individual chapters discuss the candidate's work along a trajectory from pre-clinical to clinical stages of these trials. It starts with the analysis and interpretation of comprehensive findings regarding patient, germline, and environmental safety of gene augmentation therapy, gathered from non-human primates, which led to important new hypotheses, regarding vector development and delivery, as well as patient management. Moving closer to Germany's first ocular gene therapy surgery, the thesis presents a careful, multi-modal analysis of Choroideremia patients' phenotypes, that factored into subject selection, validated the trial design, and helped to further define this rare disease. Spurred by the challenge to define novel clinical endpoints, and based on the phenotype, which was characterized in the second section, this work concludes with the investigation of a recent, computer-based colour vision test in treatment candidates, to establish its adequacy as an endpoint in retinal gene therapy trials. This dissertation is complemented by multiple reviews regarding inherited retinal disorders, as well as multiple second- and co- authorships in related literature. In its entirety, this thesis aims to paint a comprehensive picture of translational efforts in the dawn of potentially transformational advances in gene therapy.