Characterization and Development of potential molecular therapies for retinal photoreceptor disease

The overall goal of this project is twofold; understanding the pathology of photoreceptor disease, and development of novel molecular therapies for treatment of retinal photoreceptor disease. Part I of my thesis project has involved study of dark-adaptation in a mouse strain lacking the photoreceptor protein known as ABCR protein (abcr-/- mouse). The ABCR protein is present along the periphery of rod outer segment discs in the retinal rod photoreceptors and plays an important role in dark-adaptation. Impairment in the activity of the ABCR protein has been associated with Stargardt disease in humans. A 1999 study by Weng et al. observed significantly slower recovery of the ERG a-wave amplitude in abcr-/- mice as compared to wildtype mice, indicating slowed dark-adaptation in the abcr-/- mice following ~45% rhodopsin bleaching. In our study, where we compared dark-adaptation between the abcr-/- and wildtype mice at much lower bleach levels, we observed a significantly faster dark-adaptation in the abcr-/- mice as compared to wildtype, a result different from the Weng et al. (1999) finding. Based on this result, we hypothesized that the primary physiological role of the ABCR protein is to promote clearance, from the disc, of minute, residual amounts of all-trans retinal, a rhodopsin bleaching product, that other mechanisms, such as thermal diffusion across the disc membrane, cannot achieve. Photoreceptor degenerative diseases such as age-related macular degeneration (AMD) lead to the loss of functional photoreceptors, and subsequently the loss of vision. However, other cells types in the retina are believed in many cases to remain intact and functional despite the loss of the photoreceptors. Part II of my thesis concerns development of molecular structures that are responsive to light and can interface with postsynaptic membrane receptors of specific types of remaining healthy retinal cells, to “bypass” the degenerated native photoreceptors and restore vision in patients affected by AMD. Through electrophysiology and visualization experiments, we have demonstrated the binding of individual components of the molecular structures in vitro. We have also developed a novel functionalized microprobe delivery system that can focally and efficiently deliver candidate test structures to receptors expressed on mammalian cells.