Abstract
Opticin is an endogenous vitreous glycoprotein that may have therapeutic potential as it has been shown that supranormal concentrations suppress preretinal neovascularization. Herein we investigated the pharmacokinetics of opticin following intravitreal injection in rabbits. To measure simultaneously concentrations of human and rabbit opticin, a selected reaction monitoring mass spectrometry assay was developed. The mean concentration of endogenous rabbit opticin in 7 uninjected eyes was measured and found to be 19.2 nM or 0.62 μg/mL. When the vitreous was separated by centrifugation into a supernatant and collagen-containing pellet, 94% of the rabbit opticin was in the supernatant. Intravitreal injection of human opticin (40 μg) into both eyes of rabbits was followed by enucleation at 5, 24, and 72 h and 7, 14, and 28 days postinjection (n = 6 at each time point) and measurement of vitreous human and rabbit opticin concentrations in the supernatant and collagen-containing pellet following centrifugation. The volume of distribution of human opticin was calculated to be 3.31 mL, and the vitreous half-life was 4.2 days. Assuming that rabbit and human opticin are cleared from rabbit vitreous at the same rate, opticin is secreted into the vitreous at a rate of 0.14 μg/day. We conclude that intravitreally injected opticin has a vitreous half-life that is similar to currently available antiangiogenic therapeutics. While opticin was first identified bound to vitreous collagen fibrils, here we demonstrate that >90% of endogenous opticin is not bound to collagen. Endogenous opticin is secreted by the nonpigmented ciliary epithelium into the rabbit vitreous at a remarkably high rate, and the turnover in vitreous is approximately 15% per day.
Highlights
Opticin is an extracellular glycoprotein that was first identified bound to the surface of vitreous collagen fibrils.[1]
It is a member of the small leucine-rich repeat proteoglycan/protein family (SLRP), and several other members of this family of extracellular matrix molecules are known to bind to collagen fibrils.[2]
It is synthesized by the nonpigmented ciliary epithelium and secreted into the vitreous cavity.[4−6] Immunohistochemical evidence suggests that opticin binds to the internal limiting membrane (ILM) on the inner surface of the retina, and the ILM appears to impede the diffusion of opticin into the neurosensory retina which contains low levels.[5,7]
Summary
Opticin is an extracellular glycoprotein that was first identified bound to the surface of vitreous collagen fibrils.[1] It is a member of the small leucine-rich repeat proteoglycan/protein family (SLRP), and several other members of this family of extracellular matrix molecules are known to bind to collagen fibrils.[2] Opticin is extensively substituted with O-linked oligosaccharides and in solution exists as a homodimer (molecular weight of core protein and associated oligosaccharides being approximately 90 kDa) dimerizing through its leucine-rich repeat domains.[3] It is synthesized by the nonpigmented ciliary epithelium and secreted into the vitreous cavity.[4−6] Immunohistochemical evidence suggests that opticin binds to the internal limiting membrane (ILM) on the inner surface of the retina, and the ILM appears to impede the diffusion of opticin into the neurosensory retina which contains low levels.[5,7] Functional work has demonstrated that opticin has antiangiogenic properties and that the underlying mechanism of action is interfering with endothelial cell adhesion to collagen.[8,9] Studies using the murine oxygeninduced retinopathy model have shown that the antiangiogenic
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