Visual Cycle Modulation as an Approach toward Preservation of Retinal Integrity

Abstract

Increased exposure to blue or visible light, fluctuations in oxygen tension, and the excessive accumulation of toxic retinoid byproducts places a tremendous amount of stress on the retina. Reduction of visual chromophore biosynthesis may be an effective method to reduce the impact of these stressors and preserve retinal integrity. A class of non-retinoid, small molecule compounds that target key proteins of the visual cycle have been developed. The first candidate in this class of compounds, referred to as visual cycle modulators, is emixustat hydrochloride (emixustat). Here, we describe the effects of emixustat, an inhibitor of the visual cycle isomerase (RPE65), on visual cycle function and preservation of retinal integrity in animal models. Emixustat potently inhibited isomerase activity in vitro (IC50 = 4.4 nM) and was found to reduce the production of visual chromophore (11-cis retinal) in wild-type mice following a single oral dose (ED50 = 0.18 mg/kg). Measure of drug effect on the retina by electroretinography revealed a dose-dependent slowing of rod photoreceptor recovery (ED50 = 0.21 mg/kg) that was consistent with the pattern of visual chromophore reduction. In albino mice, emixustat was shown to be effective in preventing photoreceptor cell death caused by intense light exposure. Pre-treatment with a single dose of emixustat (0.3 mg/kg) provided a ~50% protective effect against light-induced photoreceptor cell loss, while higher doses (1–3 mg/kg) were nearly 100% effective. In Abca4-/- mice, an animal model of excessive lipofuscin and retinoid toxin (A2E) accumulation, chronic (3 month) emixustat treatment markedly reduced lipofuscin autofluorescence and reduced A2E levels by ~60% (ED50 = 0.47 mg/kg). Finally, in the retinopathy of prematurity rodent model, treatment with emixustat during the period of ischemia and reperfusion injury produced a ~30% reduction in retinal neovascularization (ED50 = 0.46mg/kg). These data demonstrate the ability of emixustat to modulate visual cycle activity and reduce pathology associated with various biochemical and environmental stressors in animal models. Other attributes of emixustat, such as oral bioavailability and target specificity make it an attractive candidate for clinical development in the treatment of retinal disease.

Rational Tuning of Visual Cycle Modulator Pharmacodynamics

“…Selective RPE65 inhibitors could be used to eliminate classic visual cycle function in such species and allow detailed examination of the intraretinal visual cycle in isolation. For patients with Stargardt disease wherein A2E is thought to be a primary contributor to macular degeneration (Sparrow and Boulton, 2005;Moiseyev et al, 2010;Charbel Issa et al, 2015;Saad and Washington, 2016), direct RPE65 inhibition by emixustat-like molecules could be therapeutically advantageous, as it was previously reported that both emixustat and its predecessor retinylamine lower A2E formation in mouse models of Stargardt disease (Maeda et al, 2011;Bavik et al, 2015). These compounds also exert beneficial effects in mouse models of diabetic retinopathy thought to be related to their ability to inhibit RPE65 (Liu et al, 2015).…”

“…This pharmacological concept was realized with the development of retinylamine, a transition state analog of the retinoid isomerization reaction (Golczak et al, 2005). A nonretinoid derivative of retinylamine, emixustat phenyl)propan-1-ol)], was developed later (Bavik et al, 2015), entering clinical trials for the treatment of dry AMD (Kubota et al, 2012(Kubota et al, , 2014. It is currently being evaluated as a treatment of other conditions, including diabetic retinopathy (NCT02753400).…”

Complement modulation in the retinal pigment epithelium rescues photoreceptor degeneration in a mouse model of Stargardt disease

“…This favors the formation of bisretinoids, such as A2E (8). Reduced bisretinoid levels have been observed in Abca4 −/− mice treated with drugs that lower circulating vitamin A or inhibit enzymes of the visual cycle (28,41,50). Combination drug therapy with both complement modulators and visual cycle inhibitors may be an effective treatment strategy for STGD1 because it targets both pathogenic mechanisms.…”

Retinoids and Retinal Diseases

“…The first highly selective and potent inhibitor discovered was retinylamine (Golczak et al 2005b). The systematic comparison of different inhibitors has been reported (Maeda et al 2006a) and, based on those results, emixustat was developed by Acucela Inc. (Bavik et al 2015), but human clinical trials have revealed significant side effects (Kubota et al 2012). Finally, recent studies have questioned the mechanism of action of emixustat and suggested that sequestration of all- trans -RAL should be considered as discussed in Section 8.5 (Figure 10 b ) (Zhang et al 2015).…”