Development of Efficacy Measures in Stargardt Mac. Dystrophy

Stargardt`s macular dystrophy (STGD) is one of the most frequent causes of degeneration of the central retina (the macula) and left untreated causes blindness in most cases. There is no treatment available, but substantial progress has been made to develop medical therapy, gene therapy and cell-based therapy for this condition. The success of future clinical trials will largely depend on how efficacy is demonstrated. Therefore, outcome measures need to be developed that can efficiently capture the therapeutic modification of the pathophysiology. Such outcome measures need to be very sensitive to therapeutic success, reproducible between patients and between clinical centers, and clinically relevant. To address these problems, the specific aims of this cross-sectional study are: 1. To investigate retinal morphology by spectral domain-OCT and fundus autofluorescence imaging and to develop compound variables derived from those imaging modalities that may serve as outcome measures for clinical trials in STGD 2. To map retinal sensitivity and to measure functional loss with microperimetry and to condense the map into one or few variables that may also serve as outcome measures for clinical trials in STGD 3. To correlate the structural and functional data and to show the functional relevance of changes in the compound variables derived from structural abnormalities. With such data, we will be in the perfect position to define outcome measures for clinical trials in STGD. Moreover, such data will turn out to be relevant for many other macular and retinal dystrophies. It is planned to prospectively enroll STGD patients and follow them by extensive phenotyping. Genetic analysis will also be obtained. All of the required methods are available at the Wilmer Eye Institute, as well as obtained IRB approval and developed standard operating procedures.

The main purpose of this project is the evaluation of new efficacy measures in Stargardt Macular Dystrophy (STGD). STGD is an inherited disorder and the most common cause for a degeneration of the central retina (macula) children and young adults leading to legal blindness. At present there is no therapy, however significant progress has been made in the development of different approaches and now gene, stem cell and pharmoco-therapy are in early clinical phases.The success of future clinical trials will largely depend on how efficacy of therapeutic intervention is demonstrated. In ophthalmology, the commonly used efficacy measure of visual acuity is problematic, because it only shows slow changes over time and clinical trials would have to be conducted for a decade in STGD to show efficacy when slowing down the degenerative process is the aim of therapy. Progress in imaging technologies of the retina such as e. g. fundus autofluorescence or spectral-domain optical coherence tomography allow to establish new efficacy variables due to optical resolution of single retinal layers down to the micrometer range. The application of spectral-domain optical coherence tomography could be shown to track disease progression in a group of patients of the Wilmer Eye Institute (Johns Hopkins University, Baltimore, U.S.A.) affected by STGD. The results of such imaging modalities will be correlated with those derived from fundus-controlled visual field testing (microperimetry) in order to show the functional relevance of such structural changes. Microperimetry itself may provide such efficacy measures.Because STGD exhibits a variety of different gene mutations involved (different genotypes) and clinical appearances (different phenotypes), and also given the fact the observational period to detect significant changes in the mentioned examinations is still unknown, the work of the original planned project has been expanded to and focused on the retro- and prospective studies investigating the natural course of STGD (The Natural History of the Progression of Atrophy Secondary to Stargardt Disease: A Retrospective and A Prospective Longitudinal Observational Study). Further details about these still ongoing studies are provided on the internet webpages www.progstar.org und www.clinicaltrials.gov (Identifier: NTC01977846).Publications of the first results of these studies are expected to be available in spring 2015.