This laboratory is appropriately titled Translational Research, as we use inherited retinal degenerations identified in the clinic as both a source of clues about retinal function and dysfunction and a target for research in therapeutic intervention. Our goal is to develop therapy for human genetic retinal neurodegenerative diseases, by studying animal models that mimic the human disease state and then use these findings to develop clinical trials of therapeutic agents. We use normal rodents and rodents that are genetically altered to mimic human retinal disease to study the characteristics (phenotype), molecular genetics, physiological mechanisms and possible treatments of inherited retinal degenerations. Our laboratory applies the techniques of light and electron microscopy, immunohistochemistry, biochemistry, and molecular biology to human and animal retinal tissue, as well as the electroretinogram (ERG) and behavioral measurements to access retinal function in animals in ways similar to those used to evaluate human vision in the clinic. These studies address human conditions of retinal and macular degenerations and age-related macular degeneration. Current efforts focus on human X-linked juvenile retinoschisis (XLRS). XLRS is an inherited disease and is a leading cause of juvenile macular degeneration in human males. It is due to mutations in the retinoschisin gene found on the X chromosome. We are working to understand the disease mechanisms that bring about retinal structural changes and neuronal synaptic signaling deficiency in a mouse model created in this laboratory section. At the same time, we are developing gene transfer therapy using a viral vector to supply a normal copy of the retinoschisin gene to the retina of patients in which it is defective. . Our current understanding is based on a study of human affected patients and on analysis of the XLRS mouse model. We have probed the biochemistry and sub-cellular localization of the retinoschisin protein and have localized RS to particular cell membrane sites of photoreceptors and synapses and measured changes in key membrane proteins in synapses. We discovered molecular interactions between retinoschisin and photoreceptor membrane phospholipids that may explain its role in neuronal structure and retinal signaling. We cloned and characterized the human gene promoter region and have identified the key regulatory sites. A detailed study of long-term disease progression in the XLRS mouse revealed significant correlations between degenerative structural changes and functional neuronal signaling abnormalities. Such studies currently are not possible in human and provide us better understanding of disease mechanisms and give clues on designing appropriate endpoint metrics for eventual human clinical trial. We showed retinal rescue of structure and function in the XLRS mouse by viral (AAV) vector retinoschisin gene transfer, and we are now characterizing appropriate intervention times in disease progression, doses and other parameters that lead to success or failure of gene transfer. We are also disigning and preparing a human AAV- retinoschisin gene transfer experiment. Clinical protocol: Clinical and Genetic Studies of X-Linked Juvenile Retinoschisis ClinicalTrials.gov Identifier: NCT00055029 The objectives of this registry are to understand the nature of the XLRS disease in order to develop appropriate treatments by characterizing the anatomical and functional characteristics of retinoschisis and ultimately generate a well-documented genotype-phenotype correlation map. A minimum of 100 males diagnosed with X-linked retinoschisis will undergo clinical examination and have their blood drawn for genotyping. Blood will also be drawn from available and consenting mothers of affected males. An eye examination will be performed and blood drawn from any symptomatic available and consenting female family members. A maximum of 500 affected males and family members may be enrolled. Sites outside of NIH are participating as referral centers to accumulate the cohort.
Showing the most recent 10 out of 25 publications
