Publications by authors named "Anne Rübsam"

11 Publications

  • Page 1 of 1

[Pharmacotherapy of Non-neovascular AMD].

Klin Monbl Augenheilkd 2019 Sep 30;236(9):1076-1080. Epub 2019 Jul 30.

Klinik für Augenheilkunde, Charité Universitätsmedizin Berlin.

Background: Non-neovascular age-related macular degeneration (AMD) is not yet treatable. This article summarises current clinical research approaches. The reasons for the current lack of success are analysed.

Methods: Literature and databank search.

Results: The number of therapeutic approaches and mechanisms is limited. Only reduction in lipofuscin containing deposits is specific for AMD. Further approaches include modulation of inflammation and neuroprotection. Confirmatory studies have failed to demonstrate efficacy in AMD, i.e. slowing or stopping AMD progression.

Discussion: To increase the probability of success for future developments, the pharmacological target space needs to be broadened. This may be achieved by application of molecular network analyses. As visual acuity is commonly not primarily affected by non-neovascular AMD, research on patient perspective is required to define reasonable target profiles for future therapies.
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http://dx.doi.org/10.1055/a-0914-3183DOI Listing
September 2019

[Peripheral Ischemia in Diabetic Retinopathy and Retinal Vein Occlusion: New Insights with Ultra-Wide-Angle Fundus Imaging and Wide-Angle Fluorescein Angiography].

Klin Monbl Augenheilkd 2018 Sep 14;235(9):974-979. Epub 2018 Sep 14.

Klinik und Poliklinik für Augenheilkunde, Charité - Universitätsmedizin Berlin, Berlin.

Background: In several diseases such as diabetic retinopathy and retinal vein occlusion, relevant pathophysiological changes take place in the retinal periphery. These changes may determine the prognosis and outcomes of therapy. Recent ultra-wide-angle camera systems promise improved and simplified visualisation of the outer periphery of the retina. This could potentially lead to novel clinical applications of these methods, with potential impact on therapy decisions.

Material And Methods: Literature and database research on ultra-wide imaging for diabetic retinopathy and retinal vein occlusion.

Results: With ultra-wide-angle angiography, it is possible to visualise up to 3.2-fold more retinal surface than conventional 7SF images (7SF: 7 standard field). Initial studies imply that diabetic changes can be found outside of the boundaries of the 7SF images. Patients with central vein occlusion have more extended and severe macular oedema and poorer visual acuity if ischemia of the periphery is more pronounced (measured by the ischemic index [ISI]). The amount of ischemia influences the size of the macular oedema, its resolution under therapy and the number of anti-VEGF injections needed to treat it.

Discussion: Ultra-wide-angle camera systems allow visualisation of the peripheral retina outside the boundaries of standard methods. Initial studies have detected potentially relevant changes in the outer periphery, which would have been missed by 7SF. Nevertheless, there have been no systematic studies on the relevance of these changes with regards to prognosis and therapeutic decisions.
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http://dx.doi.org/10.1055/a-0667-0706DOI Listing
September 2018

A Triple Mutation of BetaB2-Crystallin is Necessary to Develop Cataract and Glaucoma.

J Clin Exp Ophthalmol 2017 Oct 27;8(5). Epub 2017 Oct 27.

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA.

Crystallins are the predominant structural proteins in the lens that are evolutionarily related to stress proteins. There are two main crystallin gene families: α-crystallins and β/γ-crystallins. α- and β-crystallins were first considered to be lens-specific, but were recently recognized also as neuronal and retinal proteins. While in the ocular lens they are responsible for the maintenance of the transparency, their function in neurons is obviously different - regulating various protective mechanisms in degenerative conditions of the central nervous system. We recently reported the correlation between a gene conversion leading to a triple mutation in the betaB2-crystallin protein and a phenotype of familial congenital cataract with a high familial incidence also of primary open angle glaucoma. Congenital cataract is the leading cause of childhood blindness and progressive neuro degeneration of the optic nerve in glaucoma accounts as the leading cause of blindness worldwide. Altered solubility and stability of crystallin proteins cause cataract formation and are directly linked to a decrease in their protective function. Thus in this study, we evaluated the functional consequences of the mutations associated with this gene conversion on beta B2-crystallin protein biochemical properties in retinal neurons. We found that only the occurrence of the triple mutation leads to decreased solubility and formation of aggregates, which as we previously demonstrated, is associated with mislocalization to the mitochondria along with decreased mitochondrial function in retinal neurons and lens epithelial cells. Our data strongly support a significant role for beta B2-crystallin in both lenticular and retinal ocular tissues and warrant further analysis of its regulation and its impact not only in cataract formation but also in retinal neurodegenerative diseases.
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http://dx.doi.org/10.4172/2155-9570.1000690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967647PMC
October 2017

Role of Inflammation in Diabetic Retinopathy.

Int J Mol Sci 2018 Mar 22;19(4). Epub 2018 Mar 22.

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI 48105, USA.

Diabetic retinopathy is a common complication of diabetes and remains the leading cause of blindness among the working-age population. For decades, diabetic retinopathy was considered only a microvascular complication, but the retinal microvasculature is intimately associated with and governed by neurons and glia, which are affected even prior to clinically detectable vascular lesions. While progress has been made to improve the vascular alterations, there is still no treatment to counteract the early neuro-glial perturbations in diabetic retinopathy. Diabetes is a complex metabolic disorder, characterized by chronic hyperglycemia along with dyslipidemia, hypoinsulinemia and hypertension. Increasing evidence points to inflammation as one key player in diabetes-associated retinal perturbations, however, the exact underlying molecular mechanisms are not yet fully understood. Interlinked molecular pathways, such as oxidative stress, formation of advanced glycation end-products and increased expression of vascular endothelial growth factor have received a lot of attention as they all contribute to the inflammatory response. In the current review, we focus on the involvement of inflammation in the pathophysiology of diabetic retinopathy with special emphasis on the functional relationships between glial cells and neurons. Finally, we summarize recent advances using novel targets to inhibit inflammation in diabetic retinopathy.
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http://dx.doi.org/10.3390/ijms19040942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5979417PMC
March 2018

Therapy Rationale for Mineralocorticoid-Receptor Antagonists, Acetazolamide and a Switch of Therapy in Nonresponders in Central Serous Chorioretinopathy.

J Ocul Pharmacol Ther 2017 04 9;33(3):141-148. Epub 2017 Mar 9.

Department of Ophthalmology, Charité-Universitätsmedizin Berlin , Berlin, Germany .

Purpose: To evaluate the efficacy of mineralocorticoid-receptor antagonists in comparison to acetazolamide and observation in the treatment of central serous chorioretinopathy.

Methods: Retrospective, interventional cohort study on 93 patients with acute or chronic central serous chorioretinopathy (37 patients: acetazolamide group, 20 patients: mineralocorticoid-receptor antagonist group, 8 patients: observation group, and 27 patients with a therapy switch between both medications). Main outcome measures were the change in best-corrected visual acuity, subretinal fluid (SRF) volume, central retinal prominence, and highest retinal prominence (HRP) at 12 weeks.

Results: HRP and SRF volume improved with statistical significance (P ≤ 0.05) after mineralocorticoid-receptor antagonist (P = 0.0000003 for the prominence, P = 0.008 for the volume) and acetazolamide (P < 0.0000001 for the prominence, P = 0.0000007 for the volume) treatment. HRP and SRF volume also improved after observation, but without statistical significance (P = 0.08 for the prominence, P = 0.72 for the volume). Corresponding visual acuity improved significantly in acetazolamide (P = 0.002) and mineralocorticoid-receptor antagonist (P = 0.03) treated patients. Interestingly, HRP and SRF volume in acetazolamide nonresponsive patients improved after switch to mineralocorticoid-receptor antagonists, whereas no benefit was seen in patients switching vice versa.

Conclusions: Both medical treatments are effective first-line treatment options for central serous chorioretinopathy. In patients who are nonresponsive to acetazolamide, therapy switch to mineralocorticoid-receptor antagonists could be beneficial.
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http://dx.doi.org/10.1089/jop.2016.0068DOI Listing
April 2017

BetaB2-crystallin mutations associated with cataract and glaucoma leads to mitochondrial alterations in lens epithelial cells and retinal neurons.

Exp Eye Res 2017 02 26;155:85-90. Epub 2017 Jan 26.

Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI, USA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Crystallin proteins are the most prominent protein of the lens and have been increasingly shown to play critical roles in other tissues, especially the retina. Members of all 3 sub-families of crystallins, alpha-, beta- and gamma-crystallins have been reported in the retina during diabetes, traumatic injury and other retinal diseases. While their specific role in the retina is still unclear and may vary, beta-crystallin proteins have been shown to play a critical role in ganglion cell survival following trauma. We recently reported the correlation between a gene conversion in the betaB2-crystallin gene and a phenotype of familial congenital cataract. Interestingly, in half of the patients, this phenotype was associated with glaucoma. Taken together, these data suggested that the mutations we recently reported could have an impact on the role of betaB2-crystallin in both lens epithelial cells and retinal neurons. Consistent with this hypothesis, we show in the current study that the gene conversion leading to an amino acid conversion lead to a loss of solubility and a change of subcellular localization of betaB2-crystallin in both cell types. While the overall observations were similar in both cell types, there were some important nuances between them, suggesting different roles and regulation of betaB2-crystallin in lens cells versus retinal neurons. The data reported in this study strongly support a significant role of betaB2-crystallin in both lenticular and retinal ocular tissues and warrant further analysis of its regulation and its impact not only in cataract formation but also in retinal neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.exer.2017.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390483PMC
February 2017

Retrospective, controlled observational case study of patients with central retinal vein occlusion and initially low visual acuity treated with an intravitreal dexamethasone implant.

BMC Ophthalmol 2016 Oct 27;16(1):187. Epub 2016 Oct 27.

Department of Ophthalmology, Camus Virchow- Klinikum, Charité-University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.

Background: Patients with initially low visual acuity were excluded from the therapy approval studies for retinal vein occlusion. But up to 28 % of patients presenting with central retinal vein occlusion have a baseline BCVA of less than 34 ETDRS letters (0.1). The purpose of our study was to assess visual acuity and central retinal thickness in patients suffering from central retinal vein occlusion and low visual acuity (<0.1) in comparison to patients with visual acuity (≥0.1) treated with Dexamethasone implant 0.7 mg for macular edema.

Methods: Retrospective, controlled observational case study of 30 eyes with macular edema secondary to central retinal vein occlusion, which were treated with a dexamethasone implantation. Visual acuity, central retinal thickness and intraocular pressure were measured monthly. Analyses were performed separately for eyes with visual acuity <0.1 and ≥0.1.

Results: Two months post intervention, visual acuity improved only marginally from 0.05 to 0.07 (1 month; p = 0,065) and to 0.08 (2 months; p = 0,2) in patients with low visual acuity as compared to patients with visual acuity ≥0.1 with an improvement from 0.33 to 0.47 (1 month; p = 0,005) and to 0.49 (2 months; p = 0,003). The central retinal thickness, however, was reduced in both groups, falling from 694 to 344 μm (1 month; p = 0.003,) to 361 μm (2 months; p = 0,002) and to 415 μm (3 months; p = 0,004) in the low visual acuity group and from 634 to 315 μm (1 month; p < 0,001) and to 343 μm (2 months; p = 0,001) in the visual acuity group ≥0.1. Absence of visual acuity improvement was related to macular ischemia.

Conclusions: In patients with central retinal vein occlusion and initially low visual acuity, a dexamethasone implantation can lead to an important reduction of central retinal thickness but may be of limited use to increase visual acuity.
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http://dx.doi.org/10.1186/s12886-016-0363-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5081977PMC
October 2016

The TetO rat as a new translational model for type 2 diabetic retinopathy by inducible insulin receptor knockdown.

Diabetologia 2017 01 4;60(1):202-211. Epub 2016 Oct 4.

Department of Ophthalmology, Charité-Universitätsmedizin Berlin Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.

Aims/hypothesis: Although the renin-angiotensin system plays an important role in the progression of diabetic retinopathy, its influence therein has not been systematically evaluated. Here we test the suitability of a new translational model of diabetic retinopathy, the TetO rat, for addressing the role of angiotensin-II receptor 1 (AT1) blockade in experimental diabetic retinopathy.

Methods: Diabetes was induced by tetracycline-inducible small hairpin RNA (shRNA) knockdown of the insulin receptor in rats, generating TetO rats. Systemic treatment consisted of an AT1 blocker (ARB) at the onset of diabetes, following which, 4-5 weeks later the retina was analysed in vivo and ex vivo. Retinal function was assessed by Ganzfeld electroretinography (ERG).

Results: Retinal vessels in TetO rats showed differences in vessel calibre, together with gliosis. The total number and the proportion of activated mononuclear phagocytes was increased. TetO rats presented with loss of retinal ganglion cells (RGC) and ERG indicated photoreceptor malfunction. Both the inner and outer blood-retina barriers were affected. The ARB treated group showed reduced gliosis and an overall amelioration of retinal function, alongside RGC recovery, whilst no statistically significant differences in vascular and inflammatory features were detected.

Conclusions/interpretation: The TetO rat represents a promising translational model for the early neurovascular changes associated with type 2 diabetic retinopathy. ARB treatment had an effect on the neuronal component of the retina but not on the vasculature.
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http://dx.doi.org/10.1007/s00125-016-4115-0DOI Listing
January 2017

Rate and Localization of Graft Detachment in Descemet Membrane Endothelial Keratoplasty.

Cornea 2016 Mar;35(3):308-12

Department of Ophthalmology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Purpose: To investigate the rate and localization of graft detachment after Descemet membrane endothelial keratoplasty.

Methods: Sixty-six consecutive cases operated between June and August 2014 at the Charité-Universitätsmedizin Berlin were examined prospectively 1 week postoperatively. A single masked observer analyzed the rate and localization of graft detachment using optical coherence tomography (OCT), and the rebubbling rate was measured. Localization of graft detachment was correlated to the incision approach. Preoperative data were correlated to the rate of graft detachment and rebubbling.

Results: Graft detachment occurred in more than 2 clock hours and with postoperative corneal edema in 33.3% and required rebubbling. In 33.3%, graft detachment occurred in more than 2 clock hours and with postoperative corneal edema and required rebubbling. The mean graft detachment rate was 8.3% per clock hour. A significantly higher graft detachment rate was noted in the inferior clock hours (21.1%, P < 0.0001, 16.7%, P = 0.003). Only higher age of the patient correlated to a higher rate of graft detachment (P = 0.022). No correlation was found between localization of graft detachment and the incision approach (P = 0.615).

Conclusions: The graft detachment rate is high after Descemet membrane endothelial keratoplasty, but detachment is usually peripheral, partial and mainly inferior and involves only a few clock hours. Only higher age of the patient is strongly associated with a higher rate of graft detachment. The incision approach is not significantly correlated with the localization of graft detachment. Therefore, the postoperative supine position of the patient seems to be of major importance.Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT02020044.
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http://dx.doi.org/10.1097/ICO.0000000000000740DOI Listing
March 2016

Rituximab preserves vision in ocular mucous membrane pemphigoid.

Expert Opin Biol Ther 2015 Jul 12;15(7):927-33. Epub 2015 May 12.

Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum , Ophthalmology , Augustenburger Platz 1, Berlin, 13353 , Germany

Objective: To study the effectiveness and safety of anti-CD20 B-cell antibody rituximab (RTX) in the treatment of ocular mucous membrane pemphigoid (MMP).

Methods: Retrospective analysis of six MMP patients receiving RTX with or without concomitant immunosuppression. RTX was administered as a high dose regimen (1000 mg/infusion, day 0 and day 14/cycle). Five patients received more than one cycle. Main outcome measure was the treatment response, defined as complete remission (CR) or partial remission (PR), monitored at 16 and 24 weeks. As secondary outcome measure, drug-related adverse events were evaluated.

Results: All patients responded within 16 weeks. Initial treatment response vanished in five of six patients at a mean of 10 months (± 4.4 standard deviation [SD]). A second cycle was initiated thereafter (interval 12 months ± 6.4 SD) resulting in CR in two of five and PR in three of five patients. One patient stabilized only when additional immunosuppression was initiated. Mean follow up was 22 months (± 8.2 SD).Two individuals experienced infusion reactions.

Conclusions: Our study adds long-term data to the very limited experience with biologicals in MMP, indicating that RTX is a promising option for patients with advanced disease. We report for the first time the high dose regimen of RTX applied in a consecutive series.
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http://dx.doi.org/10.1517/14712598.2015.1046833DOI Listing
July 2015

Chloroquine activates the p53 pathway and induces apoptosis in human glioma cells.

Neuro Oncol 2010 Apr 27;12(4):389-400. Epub 2010 Jan 27.

The Translational Neurooncology Research Group, Department of Neurosurgery, Georg-August University Göttingen, Robert-Koch-Strasse 40, 37075 Göttingen, Germany.

Glioblastoma is the most common malignant brain tumor in adults. The currently available treatments offer only a palliative survival advantage and the need for effective treatments remains an urgent priority. Activation of the p53 growth suppression/apoptotic pathway is one of the promising strategies in targeting glioma cells. We show that the quinoline derivative chloroquine activates the p53 pathway and suppresses growth of glioma cells in vitro and in vivo in an orthotopic (U87MG) human glioblastoma mouse model. Induction of apoptosis is one of the mechanisms underlying the effects of chloroquine on suppressing glioma cell growth and viability. siRNA-mediated downregulation of p53 in wild-type but not mutant p53 glioblastoma cells substantially impaired chloroquine-induced apoptosis. In addition to its p53-activating effects, chloroquine may also inhibit glioma cell growth via p53-independent mechanisms. Our results clarify the mechanistic basis underlying the antineoplastic effect of chloroquine and reveal its therapeutic potential as an adjunct to glioma chemotherapy.
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http://dx.doi.org/10.1093/neuonc/nop046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940600PMC
April 2010