The role of Lipofuscin in STGD and dry AMD
Lipofuscin is a metabolic waste product deposited during life in various non-dividing tissues of the body. The retinal pigment epithelium (RPE) is such a non-dividing cell layer in the back of the eye and it accumulates lipofuscin.
Lipofuscin deposits in RPE cells together with drusen formation is one of the hallmarks of Stargardt disease (STGD) and dry age-related macular degeneration (dry AMD) pathogenesis. In human eyes, lipofuscin comes to occupy a substantial fraction of the RPE cytoplasmic volume. This occurs in all of us with age or in young people due to a genetic defect leading to Stragardt disease.
RPE cells represent a mono cell layer with extremely high metabolic rates. Their function includes the recycling of visual cycle products as well as the supply and waste disposal of the metabolism of the outer retina. The pathogenesis of STGD and dry AMD is today seen as a degeneration of RPE cells followed by atrophy of the photoreceptor cells in both diseases eventually leading to irreversible loss of vision.
Lipofuscin granules in a fluorescent image of RPE cells represented by the bright yellow color (image courtesy of U. Schraermeyer)
Lipofuscin accumulation is associated with a number of negative effects in literature. These include compromised lysosomal function (lysosomes being cellular organelles containing enzymes to break up cellular debris) and reduced rod outer segment phagocytosis. Also, lipofuscin accumulation has been demonstrated to be linked to increased phototoxicity and reduced antioxidant capacities of RPE cells. Lipofuscin accumulation has been shown to induce complement activation, thereby triggering inflammatory processes. Further reported negative effects comprise a detergent-like effect on cellular membranes, the release of pro-apoptotic proteins from mitochondria, and the perturbation of cholesterol metabolism in RPE cells.
Removal of Lipofuscin with Remofuscin
Remofuscin has the surprising characteristic of removing lipofuscin from living cells in the retinal pigment epithelium (RPE). This paradigm-breaking effect was previously believed to be impossible.
It has meanwhile been confirmed in various species including mouse and primate models as well as human RPE cells.
Katairo's Remofuscin development builds on the hypothesis, that removing lipofuscin may demonstrate a regenerating effect on RPE cells. While existing approaches targeting lipofuscin have tried and are still trying to limit additional accumulation of lipofuscin, Remofuscin goes a step further by reducing existing deposits - and by significant amounts as could be shown in animal models.
RPE cells before and after Remofuscin treatment. Arrows: Lipofuscin is present before treatment. Arrowheads: Lipofuscin granules are largely gone after treatment (Image courtesy of U. Schraermeyer)
Hoyng et al 2019 "Designing a Clinical Trial to Evaluate the Safety and Efficacy of Oral Soraprazan in Stargardt Disease"
Dhooge et al 2019 "Planning a Clinical Trial with Soraprazan for the Treatment ofStargardt Disease: Using a Patient-Specific Database"
Julien & Schraermeyer 2012 "Lipofuscin can be eliminated from the retinal pigment epithelium of monkeys."