Macular Degeneration: Krohne TU

Finger RP, Krohne TU, Charbel Issa P, Fleckenstein M, Scholl HP, Holz FG. · No affiliation provided · Retina. · Pubmed #19430277 No free full text.

This publication has no abstract.

Eter N, Krohne TU, Holz FG. · Department of Ophthalmology, University of Bonn Medical Center, Bonn, Germany. · BioDrugs. · Pubmed #16724865 No free full text.

Abstract: As a result of a better understanding of molecular mechanisms, a variety of new pharmacologic treatments have recently been developed for patients with age-related macular degeneration (AMD). Efficacy and tolerability have been demonstrated for drugs targeting vascular endothelial growth factor (VEGF), a key player in the pathogenesis of choroidal neovascularization. Both pegaptanib (anti-VEGF aptamer) and ranibizumab (anti-VEGF antibody fragment), applied at 4- to 6-week intervals into the vitreous, modified the natural course of the disease in phase III clinical studies. Corticosteroids with anti-angiogenic properties also represent a treatment option for wet AMD. Both intravitreal triamcinolone and anecortave acetate, administered juxtasclerally, are currently being pursued.The combination of different treatment strategies and potential synergistic effects offers new perspectives. While photodynamic therapy (PDT) combined with intravitreal triamcinolone is already frequently applied, other combinations (e.g. anti-VEGF drugs with PDT or antifibrotic agents) appear to be attractive alternatives. Pigment epithelium-derived factor represents another potential target, as well as inhibitors of matrix-metallo-proteinases. With the advent of gene therapy, the use of small interfering RNA (siRNA) is also on the horizon.Prophylactic measures are still limited. The combination of vitamins C and E, beta-carotene, and zinc as used in the AREDS (Age-Related Eye Disease Study) reduces risk for conversion from early- to late-stage disease in patients with high-risk features, at least to some extent. Lutein and zeaxanthin dietary supplements for improvement of macular pigment density need to be investigated in future longitudinal trials.

Fauser S, Krohne TU, Kirchhof B, Joussen AM. · Abteilung für Netzhaut- und Glaskörperchirurgie des Zentrums für Augenheilkunde und Zentrum für Molekulare Medizin, Universität zu Köln. · Klin Monatsbl Augenheilkd. · Pubmed #12953154 No free full text.

Abstract: The current clinical classification into focal, diffuse, and ischaemic maculopathy is useful with respect to pathomechanism and therapy. This review discusses the value of standard therapeutical options as well as the recent surgical and pharmacological approaches.

Krohne TU, Fauser S, Kirchhof B, Joussen AM. · Abteilung für Netzhaut- und Glaskörperchirurgie des Zentrums für Augenheilkunde und Zentrum für Molekulare Medizin, Universität zu Köln, Germany. · Klin Monatsbl Augenheilkd. · Pubmed #12953153 No free full text.

Abstract: Hyperglycaemia causes breakdown of the blood retina barrier leading to formation of macular oedema and consecutive visual loss. Three major mechanisms are involved in barrier breakdown: increased paracellular permeability of vascular endothelium due to disruption of cell junctions, loss of endothelial cell layer integrity due to cell destruction, and increased transcellular transport through the endothelium. This review focuses on the molecular basis of these mechanisms and discusses the role of cytokines and cellular interactions in blood retina barrier breakdown.

Fauser S, Engelmann K, Krohne TU, Lappas A, Kirchhof B, Joussen AM. · Abteilung für Netzhaut- und Glaskörperchirurgie und Zentrum für Molekulare Medizin, Universität zu Köln, Cologne. · Ophthalmologe. · Pubmed #12682762 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the developed world but the pathogenesis remains poorly understood.Malfunction of the retinal pigment epithelium (RPE) plays a central role in the disease and leads to either choriodal atrophy or proliferation.This article reviews the current concepts of the development of choriodal atrophy and neovascularisation. Furthermore, available animal models and potential therapeutical targets are discussed.

Krohne TU, Hunt S, Holz FG. · Department of Ophthalmology, University of Bonn, Ernst-Abbe-Str. 2, D-53127 Bonn, Germany. · Br J Ophthalmol. · Pubmed #18952645 No free full text.

Abstract: BACKGROUND: Translocation of an autologous retinal pigment epithelium (RPE) sheet under the macula is currently under investigation as a treatment for exudative AMD. Excimer laser-assisted RPE sheet translocation (EST) employs intraocular excimer ablation of excess graft choroidal tissue as a measure to enhance RPE sheet functionality. This study assessed potential adverse effects of excimer irradiation on RPE cells in vitro. METHODS: Human RPE cells (ARPE-19) received 308 nm XeCl excimer laser treatment or 311-312 nm UV-B irradiation. Cell death was visualised with Trypan Blue and quantified by LDH release assay. Apoptosis was detected by DNA fragmentation assay. RESULTS: Laser treatment of 0.175-0.25 J/cm(2) resulted in delayed cell death within 48 h. Time course and dose response paralleled the effect of UV-B irradiation. Cytotoxicity was mediated by apoptosis. Human choroid/Bruch membrane tissue sheets covering the cells during laser irradiation reduced cytotoxicity by 87-95%. CONCLUSION: Cultured human RPE cells are susceptible to apoptotic cell death induced by 308 nm excimer laser irradiation. Absorption by choroid/Bruch membrane tissue can largely prevent the cytotoxic effect. In clinical application, the residual adverse effect of laser ablation on graft RPE cell viability needs to be outweighed by potential advantageous effects on graft survival and functionality to allow for a sensible application of excimer ablation in RPE translocation surgery.

Krohne TU, Eter N, Holz FG, Meyer CH. · Department of Ophthalmology, University of Bonn, Bonn, Germany. · Am J Ophthalmol. · Pubmed #18635152 No free full text.

Abstract: PURPOSE: To investigate intraocular concentrations and pharmacokinetics of bevacizumab after a single intravitreal injection in humans. DESIGN: Prospective, noncomparative, interventional case series. METHODS: We included 30 nonvitrectomized eyes of 30 patients (age range, 43 to 93 years) diagnosed with clinically significant cataract and concurrent macular edema secondary to neovascular age-related macular degeneration, diabetic retinopathy, or retinal venous occlusion in the same eye. All patients received an intravitreal injection of 1.5 mg bevacizumab. Between one and 53 days after injection, an aqueous humor sample was obtained during elective cataract surgery. Concentrations of unbound bevacizumab in these samples were quantified by enzyme-linked immunosorbent assay. RESULTS: Concentration of bevacizumab in aqueous humor peaked on the first day after injection with a mean concentration (c(max)) of 33.3 microg/ml (range, 16.6 to 42.5 microg/ml) and subsequently declined in a monoexponential fashion. Nonlinear regression analysis determined an elimination half-time (t(1/2)) of 9.82 days (R(2) = 0.81). No significant differences between diagnosis subgroups were noted. CONCLUSIONS: In human nonvitrectomized eyes, the aqueous half-life of 1.5 mg intravitreally injected bevacizumab is 9.82 days.

Kaemmerer E, Schutt F, Krohne TU, Holz FG, Kopitz J. · Department of Pathology, University of Heidelberg, Heidelberg, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #17325182 links to  free full text

Abstract: PURPOSE: Lipofuscin accumulation in the RPE is a common downstream pathogenic pathway in various monogenic and complex retinal diseases including age-related macular degeneration (AMD). Lipid peroxidation-induced modification of proteins is thought to play a role in lipofuscinogenesis and may contribute to RPE dysfunction. A prior study demonstrated that a variety of lipofuscin-associated proteins are damaged by aberrant covalent modifications of malondialdehyde (MDA) and 4-hydroxynonenal (HNE). The present study was conducted to test the hypothesis that these damaged proteins are more resistant to proteolytic attack and act as protease inhibitors. METHODS: Isolated photoreceptor outer segments (POS) were radioactively labeled and in vitro modified with MDA and HNE. Pure lysosomal fractions isolated from human RPE were tested for their proteolytic activities toward modified and unmodified POS proteins. In parallel, modified and radiolabeled POS were fed to RPE cell cultures for phagocytosis and their lysosomal degradation as well as intracellular accumulation was compared with unmodified POS. RESULTS: Both experimental approaches revealed that MDA or HNE modifications strikingly increase the resistance of POS proteins to the attack by lysosomal proteases. When cultured RPE cells were fed with modified or unmodified POS the amount of degraded POS proteins was reduced by approximately 60% to 70% for the modified POS compared with those in normal control subjects. Some of the modified proteins remained undegraded in the lysosomal compartment of cultured RPE cells and were still detectable 3 weeks after feeding, whereas unmodified POS were completely degraded within 1 week after feeding. Moreover, modified proteins had the potential to impair degradation of unmodified proteins, indicating their efficacy as proteolytic antagonists. CONCLUSIONS: The results indicate that lipid peroxidation-derived protein modifications are involved in lipofuscinogenesis and may contribute to cell damaging effects of lipofuscin in retinal diseases such as AMD.