Preclinical results of a new pharmacological therapy approach for Stargardt disease and dry age-related macular degeneration

Abstract

Purpose : Stargardt disease (SD) and dry age-related macular degeneration (AMD) are marked by the accumulation of lipofuscin in the retinal pigment epithelium (RPE). This results in the progressive deterioration of the RPE and of the retina leading to vision loss and finally blindness. Thus, removal of lipofuscin from the RPE may be a potential strategy to ameliorate the clinical symptoms. Currently no treatment is available for both diseases.
We discovered that a small molecule belonging to the tetrahydropyridoether class of compounds (Remofuscin^®) is able to remove lipofuscin from the RPE. Several compounds have been shown to decrease the new formation of lipofuscin but our approach is the only one known to remove existing lipofuscin efficiently. This has already been verified in monkeys after a one-year oral treatment without showing any obvious side-effect (Julien & Schraermeyer, 2012, doi: 10.1016/j.neurobiolaging.2011.12.009).
Here we present pre-clinical data performed in SD mouse models, the pigmented and albino Abca4^-/- mice as well as the Abca4^-/-.Rdh8^-/- mice, after intravitreal injection of Remofuscin^®.

Methods : Four weeks after a single intravitreal injection of Remofuscin^® as suspension or vehicle, lipofuscin amount was quantified by measuring the fundus autofluorescence in living animals using scanning laser ophthalmoscopy (SLO) and electron microscopy. Functionality and survival rate of the photoreceptors were investigated by using electroretinography (ERG) and histology. In addition, electron microscopic autoradiography was performed in order to investigate the uptake and ocular distribution of Remofuscin^®.

Results : Efficacy of Remofuscin^® by removing lipofuscin and absence of toxicity in the ERG were confirmed in the SD mouse models. We also showed a rescue of photoreceptors in aged Abca4-/-.Rdh8-/- mice four weeks after a single intravitreal injection of Remofuscin^®.
In addition, we found that Remofuscin^® accumulates specifically within RPE pigment granules and not in choroidal melanocytes.

Conclusions : Remofuscin^® treatment is able to remove lipofuscin from the RPE, does not show any toxicity in ERG and induces a rescue of photoreceptors in SD mice. Moreover, Remofuscin^® accumulates specifically in RPE pigments. Therefore it is a promising drug for the treatment of SD and dry AMD.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.