title: 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.
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Claes
authors.initials: C
authors.lastname: Bavik
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Susan Hayes
authors.initials: SH
authors.lastname: Henry
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Mitts
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Tim
authors.initials: T
authors.lastname: McGinn
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Ewa
authors.initials: E
authors.lastname: Budzynski
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Andriy
authors.initials: A
authors.lastname: Pashko
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Kuo Lee
authors.initials: KL
authors.lastname: Lieu
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Sheng
authors.initials: S
authors.lastname: Zhong
authors.affiliation: University of California, Irvine, School of Biological Sciences, 4351 Natural Sciences II, Irvine, California 92697, United States of America.
authors.forename: Bruce
authors.initials: B
authors.lastname: Blumberg
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Kuksa
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Mark
authors.initials: M
authors.lastname: Orme
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Ian
authors.initials: I
authors.lastname: Scott
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Fawzi
authors.affiliation: Acucela, Inc., 1301 2nd Avenue, Suite 1900, Seattle, Washington 98101, United States of America.
authors.forename: Ryo
authors.initials: R
authors.lastname: Kubota
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000172:deficiency / Q000235:genetics; D000818:Animals; D004195:Disease Models, Animal; D004596:Electroretinography; D015870:Gene Expression; D008027:Light; D008062:Lipofuscin / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D010647:Phenyl Ethers / Q000494:pharmacology*; D011412:Propanolamines / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012176:Retinoids / Q000037:antagonists & inhibitors / Q000378:metabolism; D012178:Retinopathy of Prematurity / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D019745:cis-trans-Isomerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099178:Retinoid Isomerohydrolase
chemical_list: D018528:ATP-Binding Cassette Transporters; D008062:Lipofuscin; D010647:Phenyl Ethers; D011412:Propanolamines; D012176:Retinoids; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase; C112040:A2-E (N-retinylidene-N-retinylethanolamine); C512841:Abca4 protein, mouse; C000592692:emixustat