Delivery of genes and drugs to the cells of the retina is a significant challenge in the treatment of retinal and other disorders. We have developed a non-invasive method that exploits electrical fields applied trans- sclerally to efficiently deliver larger amounts of RNA or DNA to the retinal pigmented epithelium (RPE). This noninvasive approach will avoid side effects that can occur with surgical subretinal viral delivery, and repeated dosing should be easy and practical. In the future, once developed in the present simple model system, these results will guide us in adapting gene therapy to ophthalmic practice to treat diseases including glaucoma and retinal and macular degenerations. The disease and gene defect selected for this study is known to be treatable in animal models, and prior work serves as guidance and as a baseline for efficacy comparisons with our delivery approach. Our DNA delivery systems are established and meet the priority function of trans-scleral DNA delivery in vitro already. The electrical fields will be refined to aid and establish starting parameters for in vivo studies. Safety studies are planned to help achieve high delivery without damage to eye tissues or the animal. Iterative improvements are made based on optimization experiments, and outcome measures are collected both in vitro and in vivo. In the latter stages of the study, efficacy data are obtained. We plan to learn when and how to prevent severe night blindness and retinal degeneration in LCA caused by mutations in RPE65 in this project. This research project has two goals. The first goal is to optimize the amounts of nucleic acids that can be driven into the RPE trans-sclerally. The second goal is to evaluate the safety and efficacy of RPE65 gene delivery and expression in vivo in mice with lesions in this gene.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
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Neuhold, Lisa
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Emory University
Schools of Medicine
United States
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Chrenek, Micah A; Nickerson, John M; Boatright, Jeffrey H (2016) Clustered Regularly Interspaced Short Palindromic Repeats: Challenges in Treating Retinal Disease. Asia Pac J Ophthalmol (Phila) 5:304-8
Schmidt, Robin H; Nickerson, John M; Boatright, Jeffrey H (2016) Exercise as Gene Therapy: BDNF and DNA Damage Repair. Asia Pac J Ophthalmol (Phila) 5:309-11
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Allen, Rachael S; Olsen, Timothy W; Sayeed, Iqbal et al. (2015) Progesterone treatment in two rat models of ocular ischemia. Invest Ophthalmol Vis Sci 56:2880-91
Boatright, Jeffrey H; Dalal, Nupur; Chrenek, Micah A et al. (2015) Methodologies for analysis of patterning in the mouse RPE sheet. Mol Vis 21:40-60

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