Age-related macular degeneration (AMD) is the leading cause of
blindness in older people in the developed world while Stargardt's disease (SD) is a
juvenile macular degeneration and an
orphan disease. Both diseases are untreatable and are marked by accumulation of
lipofuscin advancing to progressive deterioration of the retinal pigment epithelium (RPE) and retina and subsequent vision loss till
blindness. We discovered that a small molecule belonging to the tetrahydropyridoether class of compounds,
soraprazan renamed
remofuscin, is able to remove existing
lipofuscin from the RPE. This study investigated the
drug penetration, distribution, and elimination into the eyes of a mouse model for increased lipofuscinogenesis, following a single
intravitreal injection. We measured the time course of concentrations of
remofuscin in different eye tissues using high-performance liquid chromatography combined with mass spectroscopy (HPLC-MS). We also visualized the penetration and distribution of 3 H-
remofuscin in eye sections up to 20 weeks post-injection using transmission electron microscopic (TEM) autoradiography. The distribution of
silver grains revealed that
remofuscin accumulated specifically in the RPE by binding to the RPE pigments (
melanin,
lipofuscin and melanolipofuscin) and that it was still detected after 20 weeks. Importantly, the melanosomes in choroidal melanocytes only rarely bind
remofuscin emphasizing its potential to serve as an active ingredient in the RPE for the treatment of SD and dry AMD. In addition, our study highlights the importance of electron microscopic autoradiography as it is the only method able to show
drug binding with a high intracellular resolution.