Apolipoprotein A-I Mimetic Peptide L-4F Removes Bruch's Membrane Lipids in Aged Nonhuman Primates

Abstract

PURPOSE. Multiple evidence lines support Bruch's membrane lipid deposition as a major precursor of soft drusen and age-related macular degeneration as including a potentially treatable atherosclerosis-like progression in the subretinal pigment epithelium (RPE)-basal lamina space. We evaluated the effect of anti-inflammatory, antiatherogenic peptide L-4F on Bruch's membrane of aged nonhuman primates in a dose-escalating study. METHODS. Macaca fascicularis ‡20 years of age evaluated by color fundus photography and optical coherence tomography received monocular intravitreal injections of L-4F (n ¼ 7) or a placebo-scrambled peptide (n ¼ 2) in 6 doses of 25 to 175 lg over 6 months. Eyes were processed for detection and masked semiquantitative assessment of macular Bruch's membrane neutral lipid (oil red O staining), esterified cholesterol (filipin histochemistry), membrane attack complex (immunofluorescence), and paramacular thickness (transmission electron microscopy). RESULTS. Bruch's membrane neutral lipid, esterified cholesterol, and membrane attack complex were cleared and ultrastructure was improved in L-4F-injected eyes, compared to placebo-injected eyes. Fellow eyes were also affected to the same degree as the injected eyes. Punctate yellow fundus lesions without corresponding RPE elevations on optical coherence tomography correlated to RPE lipoidal degeneration (engorgement with lipid droplets), which was unchanged by this treatment. CONCLUSIONS. Clinical-stage apolipoprotein A-I mimetic peptide L-4F, delivered intravitreally in repeated doses, produced a substantial pharmacologic reduction of Bruch's membrane lipid and restoration of ultrastructure in a nonhuman primate model that exhibits an important precursor of soft drusen, if not soft drusen themselves.

Type 1 Choroidal Neovascularization Is Associated with Reduced Localized Progression of Atrophy in Age-Related Macular Degeneration

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Evaluating diurnal changes in choroidal sublayer perfusion using optical coherence tomography angiography

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LXRs regulate features of age-related macular degeneration and may be a potential therapeutic target

“…Although eyes from WT mice exhibited normal RPE-choroid morphology with organized basal infoldings and apical processes of the RPE(Figure 5, M and N), in Nr1h3 -/mice, continuous sub-RPE deposits were observed below disrupted basal infoldings, seen as amorphous, electron-dense material, interspersed with "streamers," a phenotype typical of early dry AMD (over 40% of the length of Bruch's membrane, BrM;Figure 5, O and P, and SupplementalFigure 12). The RPE phenotype of Nr1h2 -/mice had distinct pathologies, including accumulation of large lipid droplets within the RPE, reminiscent of lipoidal degeneration, which is not a characteristic of AMD (Figure 5, Q and R, and refs 27,28)…”