Macular Degeneration: Jaissle GB

Jaissle GB, Ziemssen F, Petermeier K, Szurman P, Ladewig M, Gelisken F, Völker M, Holz FG, Bartz-Schmidt KU. · Abt. I, Universitätsaugenklinik Tübingen, Schleichstrasse 12, 72076 Tübingen. · Ophthalmologe. · Pubmed #16763863 No free full text.

Abstract: Application of VEGF inhibitors represents a treatment option for macular edema secondary to retinal vein occlusion that targets the disease at the causal molecular level. First reports on intravitreal injections of bevacizumab show promising morphological and functional effects and demonstrate that bevacizumab is a potent antiedematous agent in this context. A significant reduction of the central retinal thickness followed by a rapid improvement of visual acuity may be achieved within days. In a pilot study with a review period of 3 months, we found a significant improvement of one or more lines in 93% and four or more lines in 27% of eyes. This was associated with a concomitant significant reduction in central retinal thickness, which, however, was not sustained by a single injection (64% reduction after 1 month and 28% after 3 months). No relevant adverse events were noted. The duration of action after intravitreal bevacizumab administration is currently unknown. Reinjections will be necessary to maintain a lasting beneficial effect. Prospective, controlled long-term studies are mandatory to develop standardized treatment protocols that allow a safe and effective application of this off-label therapy.

Jaissle GB, Leitritz M, Gelisken F, Ziemssen F, Bartz-Schmidt KU, Szurman P. · University Eye Clinic, Centre for Ophthalmology, Eberhard-Karls University of Tuebingen, Schleichstr. 12, 72076 Tuebingen, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #18696094 No free full text.

Abstract: BACKGROUND: To investigate the long-term effectiveness of intravitreal bevacizumab treatment in eyes with perfused macular edema due to branch retinal vein occlusion (BRVO). METHODS: In this prospective interventional case series, 23 consecutive, previously untreated eyes with perfused macular edema were treated with intravitreal bevacizumab (1.25 mg) injections and followed for 1 year. The main outcome measures were visual acuity (VA) and central retinal thickness (CRT). In addition, VA data were adapted to the non-logarithmic VA charts used in the previously published grid laser photocoagulation BRVO Study. RESULTS: The median VA gained 3.0 lines from baseline at 48 weeks. This was accompanied by a significant decrease of 39% of the median CRT. The mean number of re-injections was 1.6 during the first 6 months of follow-up and only 0.8 during the subsequent 6 months. In 65% of the cases, adapted VA data showed a gain of 1 or more lines and no eye lost more than 1 line. CONCLUSIONS: Repetitive intravitreal bevacizumab injections result in a significant long-term improvement of VA and CRT. The number of re-injections necessary to maintain this effect declined over time. However, the treatment seems to be only slightly better than grid laser photocoagulation.

Weber BH, Lin B, White K, Kohler K, Soboleva G, Herterich S, Seeliger MW, Jaissle GB, Grimm C, Reme C, Wenzel A, Asan E, Schrewe H. · Institute of Human Genetics, Biocenter, University of Wuerzburg, Germany. · Invest Ophthalmol Vis Sci. · Pubmed #12147610 links to  free full text

Abstract: PURPOSE: Sorsby fundus dystrophy (SFD) is a rare, late-onset macular dystrophy caused by mutations in the tissue inhibitor of metalloproteinases-3 (TIMP3) gene. The known mutations introduce potentially unpaired cysteine residues in the C terminus of the protein and result in the formation of higher-molecular-weight protein complexes of as yet unknown composition and functional consequences in the pathologic course of SFD. To facilitate in vivo investigation of mutant TIMP3, the authors generated a knock-in mouse carrying a disease-related Ser156Cys mutation in the orthologous murine Timp3 gene. METHODS: Site-directed mutagenesis and homologous recombination in embryonic stem (ES) cells was used to generate mutant ES cells carrying the Timp3(S156C) allele. Chimeric animals were obtained, of which two displayed germline transmission of the mutated allele. Molecular genetic, biochemical, electron microscopic, and electrodiagnostic techniques were used for characterization. RESULTS: At 8 months of age, knock-in mice showed abnormalities in the inner aspect of Bruch's membrane and in the organization of the adjacent basal microvilli of the retinal pigment epithelium (RPE). Changes resembling those in the mutant animals were also present to some extent in normal littermates, but only at an advanced age of 30 months. Long-term electrodiagnostic recordings indicated normal retinal function throughout life. The biochemical characteristics of the mutant protein appear similar in humans and knock-in mice, suggesting common molecular pathways in the two species. The localization of the mutant protein in the eye is normal, although there is evidence of increased Timp3 levels in Bruch's membrane of mutant animals. CONCLUSIONS: The knock-in mice display early features of age-related changes in Bruch's membrane and the RPE that may represent the primary clinical manifestations of SFD. In addition, our immunolabeling studies and biochemical data support a model proposing that site-specific excess rather than absence or deficiency of functional Timp3 may be the primary consequence of the known Timp3 mutations.

Weber BH, Schrewe H, Molday LL, Gehrig A, White KL, Seeliger MW, Jaissle GB, Friedburg C, Tamm E, Molday RS. · Institute of Human Genetics, Biocenter, University of Würzburg, D-97074 Würzburg, Germany. · Proc Natl Acad Sci U S A. · Pubmed #11983912 links to  free full text

Abstract: Deleterious mutations in RS1 encoding retinoschisin are associated with X-linked juvenile retinoschisis (RS), a common form of macular degeneration in males. The disorder is characterized by a negative electroretinogram pattern and by a splitting of the inner retina. To gain further insight into the function of the retinoschisin protein and its role in the cellular pathology of RS, we have generated knockout mice deficient in Rs1h, the murine ortholog of the human RS1 gene. We show that pathologic changes in hemizygous Rs1h(-/Y) male mice are evenly distributed across the retina, apparently contrasting with the macula-dominated features in human. Similar functional anomalies in human and Rs1h(-/Y) mice, however, suggest that both conditions are a disease of the entire retina affecting the organization of the retinal cell layers as well as structural properties of the retinal synapse.