Retinal Toxicity Induced by a Novel β-secretase Inhibitor in the Sprague-Dawley Rat

Abstract

b-Secretase 1 (BACE1) represents an attractive target for the treatment of Alzheimer's disease. In the course of development of a novel small molecule BACE1 inhibitor (AMG-8718), retinal thinning was observed in a 1-month toxicity study in the rat. To further understand the lesion, an investigational study was conducted whereby rats were treated daily with AMG-8718 for 1 month followed by a 2-month treatment-free phase. The earliest detectable change in the retina was an increase in autofluorescent granules in the retinal pigment epithelium (RPE) on day 5; however, there were no treatment-related light microscopic changes observed in the neuroretina and no changes observed by fundus autofluorescence or routine ophthalmoscopic examination after 28 days of dosing. Following 2 months of recovery, there was significant retinal thinning attributed to loss of photoreceptor nuclei from the outer nuclear layer. Electroretinographic changes were observed as early as day 14, before any microscopic evidence of photoreceptor loss. BACE1 knockout rats were generated and found to have normal retinal morphology indicating that the retinal toxicity induced by AMG-8718 was likely off-target. These results suggest that AMG-8718 impairs phagolysosomal function in the rat RPE, which leads to photoreceptor dysfunction and ultimately loss of photoreceptors.

BACE1 across species: a comparison of the in vivo consequences of BACE1 deletion in mice and rats

“…In this study, Fielden et al 22. showed that an ocular phenotype involving thinning of the retina in Bace1 −/− mice23 is not observed in Bace1 −/− rats.…”

“…Most reports are based on Bace1 −/− mice and there is only one published report of a BACE1 knockout rat model22. In this study, Fielden et al 22.…”

“…Indeed, if the question arises if a toxicology finding in rats is on-target or not, the definitive proof that the finding is off-target would be a persistence of that finding in knockout animals dosed with the same drug. To date only one published study on BACE1 null animals examined rats22. Yet, cross-species in vivo studies are urgently needed since BACE1 inhibition is an important therapeutic approach for AD in humans34.…”

“…showed that an ocular phenotype involving thinning of the retina in Bace1 −/− mice23 is not observed in Bace1 −/− rats. While Fielden et al 22. focused on ocular readouts, this raises the more general question of how well other findings in BACE1 null mice may translate to rats and possibly other species, or if they are unique to the mouse species or specific strain in a given study.…”

Physiological Functions of the β-Site Amyloid Precursor Protein Cleaving Enzyme 1 and 2

“…The role of BACE1 in retinal pathophysiology has gained increasing attention in recent years, as several BACE1 inhibitors have been found to cause retinal thinning, lipofuscin accumulation, and vascular dysfunction, which terminated clinical trials (Fielden et al, 2015). BACE1 was initially suggested to mediate these retinopathies in a report that BACE1-null mice were found to develop retinal thinning, apoptosis, reduced retinal vascular density, and an increase in age pigmentation and lipofuscin (Cai et al, 2012).…”