Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment - PubMed (original) (raw)

Pharmacological inhibition of lipofuscin accumulation in the retina as a therapeutic strategy for dry AMD treatment

Konstantin Petrukhin. Drug Discov Today Ther Strateg. 2013.

Abstract

Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. There is no FDA-approved treatment for the most prevalent dry (atrophic) form of AMD. Photoreceptor degeneration in dry AMD is triggered by abnormalities in the retinal pigment epithelium (RPE). It has been suggested that excessive accumulation of fluorescent lipofuscin pigment in the RPE represents an important pathogenic factor in etiology and progression of dry AMD. Cytotoxic lipofuscin bisretinoids, such as A2E, are formed in the retina in a non-enzymatic way from visual cycle retinoids. Inhibition of toxic bisretinoid production in the retina seems to be a sound treatment strategy for dry AMD. In this review we discuss the following classes of pharmacological treatments inhibiting lipofuscin bisretinoid formation in the retina: direct inhibitors of key visual cycle enzymes, RBP4 antagonists, primary amine-containing aldehyde traps, and deuterated analogs of vitamin A.

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Conflict of interest statement

Conflict of interest statement

Columbia University owns IP rights to ophthalmic use of A1120 and its derivatives

Figures

Figure 1

Figure 1. The visual cycle and points of intervention for pharmacological inhibition of lipofuscin bisretinoid synthesis in the retina

Enzymes and transporters facilitating visual cycle reactions in photoreceptor outer segments are highlighted in green. Enzymes catalyzing visual cycle reactions conducted in the RPE are shown in orange. Lipofuscin bisretinoid biosynthesis begins when all-trans-retinal leaves the visual cycle and non-enzymatically reacts with phosphatidylethanolamine forming the A2E precursor, A2-PE (blue arrow); 11-cis-retinal is also reported to be a precursor of A2E formation [30] (dotted arrow). Uptake of serum retinol to the RPE (red arrow) fuels the visual cycle. Highlighted in bright blue are four intervention points for suppression of lipofuscin bisretinoid formation: inhibition of key visual cycle enzymes such as RPE65, neutralization of free aldehydes, suppression of bisretinoid formation with deuterated vitamin A analogs, and reduction of retinol uptake to the retina with RBP4 antagonists. Abbreviations: ABCA4, retina-specific ABC transporter; all-trans-RDH, all-trans-retinol dehydrogenase; LRAT, lecithin-retinol acyltransferase; 11-cis-RDH, 11-cis-retinol-dehydrogenase.

Figure 2

Figure 2. Structure of compounds exemplifying four classes of treatments capable of reducing lipofuscin bisretinoid production in animal models of enhanced retinal lipofuscinogenesis

A, Structure of the RPE65 inhibitor ACU-4429 as can be inferred from the US 2011/0003895-A1 patent application. A1120 (B) and fenretinide (C) exemplify the class of RBP4 antagonists. Racemic mixture of two primary amine-containing pegabalin stereoisomers (D) acts as an aldehyde trap. E, a deuterated C20-D3 vitamin A analog in a form of retinyl acetate.

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