Optimization of treatment flow to improve performance of retinal gene therapy

点击翻译按钮获取中文摘要

Gene therapy of the retina is a novel tool for the treatment of inherited retinal degenerations. Preclinical studies from several groups world-wide including our own clearly show the promise of this approach to provide a cure for this potentially blinding group of diseases. Following a relatively fast advancement from bench to bedside, several clinical studies have been started in the immediate past and further human trials are in preparation. While traditionally the focus in this field is on the expansion of therapeutic indications and vector development, opportunities for the optimization of treatment flow have at best received moderate attention. We believe, however, that quite substantial improvements in the efficacy and longevity of curative effects may be accomplished this way. A key, seminal part of the treatment is the subretinal injection. The general believe is that retina and RPE separate at the time of the injection and come together again after the bleb has resolved, which has been observed to take hours to a few days. However, there is to our best knowledge no comprehensive data on presumably influential parameters like best volume for injections, size of bleb/local pressure characteristics, and optimal time of day/conformance with circadian rhythm. In murine models, we have conducted preliminary studies in this regard using a standardized protocol developed over the past years. We found that the morphological ultrastructure at the subretinal injection site was much more compromised than previously thought. In particular, we found that subretinal injections regularly rupture photoreceptor outer segments instead of pulling them out of the retina/RPE interface. Based on our preliminary data, we further conducted a pilot study in an attempt to optimize the time point for injections. In particular, we aimed to take advantage of presumed mechanical fluctuations in RPE/retina bonds, which allegedly are minimal at the time of disc shedding. Indeed, we found that injections at the expected time of disc shedding produced considerable less damage than those 12h later. In this proposal, we explore options to improve the treatment procedure via an optimal synchronization with the circadian rhythm in order to achieve a superior outcome for a given therapy. Besides acute effects on morphology, we will study the long-term outcome in disease models for human inherited retinal degenerations, and assess whether the favorable effect observed is dependent on rod or cone vision. As the observation of photoreceptor disc shedding in the living human eye has recently been demonstrated, a circadian rhythm-synchronized treatment will certainly become possible soon in a clinical setting.