Fructosamine-3-Kinase as a Potential Treatment Option for Age-Related Macular Degeneration

Abstract

Age-related macular degeneration is the leading cause of blindness in the developed world. Since advanced glycation end products (AGEs) are implicated in the pathogenesis of AMD through various lines of evidence, we investigated the potential of fructosamine-3-kinase (FN3K) in the disruption of retinal AGEs, drusenoid material and drusenoid lesions in patients with AMD. AGE-type autofluorescence was measured to evaluate the effects of FN3K on glycolaldehyde-induced AGE-modified neural porcine retinas and unmodified human neural retinas. Eye pairs from cigarette-smoke- and air-exposed mice were treated and evaluated histologically. Automated optical image analysis of human tissue sections was performed to compare control- and FN3K-treated drusen and near-infrared (NIR) microspectroscopy was performed to examine biochemical differences. Optical coherence tomography (OCT) was used to evaluate the effect of FN3K on drusenoid deposits after treatment of post-mortem human eyes. FN3K treatment provoked a significant decrease (41%) of AGE-related autofluorescence in the AGE-modified porcine retinas. Furthermore, treatment of human neural retinas resulted in significant decreases of autofluorescence (−24%). FN3K-treated murine eyes showed less drusenoid material. Pairwise comparison of drusen on tissue sections revealed significant changes in color intensity after FN3K treatment. NIR microspectroscopy uncovered clear spectral differences in drusenoid material (Bruch’s membrane) and drusen after FN3K treatment. Ex vivo treatment strongly reduced size of subretinal drusenoid lesions on OCT imaging (up to 83%). In conclusion, our study demonstrated for the first time a potential role of FN3K in the disruption of AGE-related retinal autofluorescence, drusenoid material and drusenoid lesions in patients with AMD.

Topical Application of Deglycating Enzymes as an Alternative Non-Invasive Treatment for Presbyopia

“…Maximal effects on lens opacity are observed in the wavelength range of 410–430 nm, which is a typical absorbance wavelength of Maillard products that induces a yellow-brownish coloration of aged lenses. Our observations strengthen our hypothesis that the process of non-enzymatic glycation of proteins such as crystallins can be reversed [ 11 , 20 ]. Several studies have demonstrated that Maillard reactions involving sugars can induce a decrease in the chaperone function of α-crystallins [ 22 , 23 , 24 , 25 ].…”

“…In general, the physicochemical behavior of enzyme molecules (such as FAOD, 49 kDa) [ 17 ] and FN3K (37 kDa) [ 18 ] in the 35–50 kDa range allows for swift diffusion in the anterior and posterior eye chambers so that intraocular targets can easily be reached [ 19 ]. Reduction in Maillard-type autofluorescence, glycation-induced aggregation, and covalent cross-linking of lens crystallins can result in a decrease in natural elasticity and an increase in stiffness [ 20 , 21 ]. Normally, the lens capsule together with the cortex, when not under the tension of the zonules, causes the lens to assume a rounded shape [ 21 ].…”

A Potential Role for Fructosamine-3-Kinase in Cataract Treatment

“…Furthermore, while FN3K appears to be active against autofluorescent AGEs, we currently do not know its potential effect on non-autofluorescent AGEs. Albeit commercial antibody-based staining protocols for AGEs are available, their applicability is rather limited since AGEs represent a heterogeneous group of compounds and the exact targets of the antibodies have not yet been established [ 24 ]. So far, dozens of AGEs have been reported in vivo, with most of them being present at increased levels in cataractous lenses [ 13 ].…”

“…As described previously [ 24 , 45 ], AGEs were quantified based on Maillard-type autofluorescence (AF) measurements (excitation 365 nm, emission 390–700 nm) using a Flame miniature spectrometer (FLAME-S-VIS-NIR-ES, 350–1000 nm, Ocean Optics, Dunedin, Florida, USA) equipped with a high-power LED light source (365 nm, Ocean Optics) and a reflection probe (QR400-7-VIS-BX, Ocean Optics). Measurements were averaged over 128 scans.…”

“…Next to the classical view of FN3K being an intracellular enzyme that has primary (low molecular mass) glycation products as a unique substrate, recent research suggested an additional potential role of FN3K in the direct disruption of retinal AGEs [ 24 ]. However, it is still unexplored whether FN3K treatment would also result in the disruption of AGEs and cross-linked structures of cataractous lenses.…”