Manipulation of photoreceptor energy metabolism for clinical advantage

Photoreceptors are metabolically active cells that account for the majority of the energy consumption in the retina. Photoreceptors also display high rates of aerobic glycolysis which is unusual in non-proliferating cells. Many diseases of the retina involve degeneration of photoreceptors. Retinitis pigmentosa is the most commonly encountered hereditary retinal dystrophy, featuring degeneration of rod photoreceptors followed by cone photoreceptors. The genetic mutations in retinitis pigmentosa are exclusively expressed in rods, and the secondary death of cones likely involves a component of energy failure. The overriding premise of this thesis was to further our understanding of photoreceptor energy metabolism, then manipulate photoreceptor energy metabolism for clinical advantage using an in vivo model of retinitis pigmentosa. The current thesis comprises three main experiments. In the first experiment, we investigated the role of glucose in the mouse retina and sought to provide an explanation for the high rate of aerobic glycolysis. This was performed by observing the distribution of carbon-14 glucose in the mouse retina using autoradiographic methods. In the second experiment, we characterized the temporal and spatial distribution of cone degeneration in a mouse model of retinitis pigmentosa. Cone quantification was performed using immunohistochemistry and reverse transcription polymerase chain reaction. In the third experiment, we tested two novel bio-energetic agents on the previously characterized mouse model of retinitis pigmentosa. Mice received either systemic creatine, delivered orally, or local glucose, delivered via repeated subconjunctival injection, and the effect on cone survival was measured using immunohistochemistry and neuro-behavioral responses. The results revealed that local glucose injections had no protective effect on cone survival. However, oral creatine treatment preserved cones and improved neuro-behavioral responses in retinal degeneration mice. Therefore, we demonstrated that cone degeneration in retinitis pigmentosa likely occurs due to a mechanism that involves, at least in part, energy failure. Bio-energetic treatments, such as creatine, may play a role as future therapies for retinitis pigmentosa. Further studies will be performed to elucidate the precise mechanisms through which creatine exerts its protective effects, prior to developing a pathway to clinical translation in human patients.Thesis (MPhil) -- University of Adelaide, Adelaide Medical School, 201