Macular Degeneration: Kvanta A

Kvanta A. · No affiliation provided · Acta Ophthalmol. · Pubmed #18752524 No free full text.

This publication has no abstract.

Kvanta A. · No affiliation provided · Acta Ophthalmol Scand. · Pubmed #17244203 No free full text.

This publication has no abstract.

Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A. · Cellular and Molecular Tumor Pathology, Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institute, Stockholm, Sweden. · Acta Ophthalmol. · Pubmed #19032681 No free full text.

Abstract: Introduction: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors like vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF-1) and its receptor, IGF-1R, have been implicated in CNV. Purpose: We have previously shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in-vivo model. In this study we investigated the effect of PPP on VEGF expression both in vitro and in vivo and whether this effect has anti-angiogenic consequences in a murine CNV model. Materials and Methods: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in choroids and retinal pigment epithelial cells (APRE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. Results: Mice treated with PPP, administered intraperitoneally or orally, showed 22-32% (p = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroids were significantly reduced. In cultured APRE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. We could confirm that PPP reduced the level of transcriptional activity of VEGF promoter. Conclusions: PPP reduces IGF-1 dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the therapy of conditions associated with CNV including neovascular AMD.

Economou MA, Wu J, Vasilcanu D, Rosengren L, All-Ericsson C, van der Ploeg I, Menu E, Girnita L, Axelson M, Larsson O, Seregard S, Kvanta A. · Cellular and Molecular Tumour Pathology, Department of Oncology and Pathology, Cancer Centre Karolinska R8:04, Karolinska Institute, Stockholm, Sweden. · Invest Ophthalmol Vis Sci. · Pubmed #18515591 links to  free full text

Abstract: INTRODUCTION: Choroidal neovascularization (CNV) is a debilitating complication of age-related macular degeneration (AMD) and a leading cause of vision loss. Along with other angiogenic factors such as vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-1 and its receptor, IGF-1R, have been implicated in CNV. PURPOSE: A prior study has shown that the cyclolignan picropodophyllin (PPP) efficiently blocks the insulin-like growth factor-1 receptor (IGF-1R) activity and causes cell death in uveal melanoma cell lines and in an in vivo model. In this study we investigated the effect of PPP on VEGF expression, both in vitro and in vivo, and whether this effect has antiangiogenic consequences in a murine CNV model. METHODS: C57BL/6J mice with laser-induced CNVs were treated with PPP. Effects on CNV area were assayed by image analysis. VEGF levels in the choroid and retinal pigment epithelial cells (ARPE-19) were measured by Western blot or ELISA. Transcriptional activation of the VEGF promoter was determined by luciferase reporter gene assay. RESULTS: Mice treated with PPP, administered intraperitoneally or orally, showed a 22% to 32% (P = 0.002) decrease in CNV area. Furthermore, VEGF levels in the choroid were significantly reduced. In cultured ARPE-19 cells, IGF-1 was shown to increase VEGF secretion. This increase was completely blocked by PPP. PPP reduced the level of transcriptional activity of the VEGF promoter. CONCLUSIONS: PPP reduces IGF-1-dependent VEGF expression and CNV in vivo. Accordingly, IGF-1R inhibitors may be useful tools in the treatment of conditions associated with CNV, including neovascular AMD.

Odergren A, Algvere PV, Seregard S, Kvanta A. · Vitreoretinal Department, Karolinska Institutet, St. Eriks Eye Hospital, Polhemsgatan 50, SE-11282 Stockholm, Sweden. · Br J Ophthalmol. · Pubmed #18356266 No free full text.

Abstract: AIM: To compare the efficacy of low-dose transpupillary thermotherapy (TTT) and verteporfin photodynamic therapy (PDT) in patients with occult neovascular age-related macular degeneration (AMD). METHODS: Patients were randomised to receive either low-dose TTT (136 mW/mm) (and sham PDT) (n = 52) or PDT (and sham TTT) (n = 46) with retreatment if leakage was documented by fluorescein angiography. At baseline and at every follow-up, best corrected visual acuity (BCVA) was measured with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart, lesion size on fluorescein angiography and foveal thickness with optical coherence tomography. The primary outcome measure was the proportion of patients who lost <15 letters at 12 months' follow-up. Secondary outcome measures included the proportion of patients who gained >/=0 letters, the change in mean lesion size and the change in foveal thickness at 12 months' follow-up. RESULTS: The percent of patients losing fewer than 15 letters at 12 months was 75.0% in the TTT group and 73.9% in the PDT group (p>0.05). The percent of patients with preserved or improved BCVA was 36.5% in the TTT group versus 23.9% in the PDT group (p>0.05). The mean decrease in foveal thickness was 15% for TTT and 24% (p>0.05) for PDT-treated patients, and the mean increase in total lesion area was -0.7% and -1.1% (p>0.05), respectively. CONCLUSION: In this prospective, randomised trial low-dose TTT and PDT appeared to be equally efficient at stabilising visual acuity in patients with occult neovascular AMD. Low-dose TTT may be considered as an alternative to PDT in this set of patients and also as an adjuvant to pharmacotherapy.

Algvere PV, Steén B, Seregard S, Kvanta A. · Karolinska Institute, St Erik's Eye Hospital, Stockholm, Sweden. · Acta Ophthalmol. · Pubmed #18162062 No free full text.

Abstract: PURPOSE: Choroidal neovascularization (CNV) accounts for 85-90% of severe visual impairment in age-related macular degeneration (AMD). Vascular endothelial growth factor (VEGF) is a major factor mediating angiogenesis, and VEGF inhibitors have become a new treatment modality. In this prospective study, we used bevacizumab (Avastin), a recombinant monoclonal antibody to VEGF, to treat neovascular AMD. METHODS: The case material comprised 36 subjects (26 females, 10 males) aged 65-88 years with subfoveal neovascular AMD with all subtypes of CNV. There were two categories of patients: category I, long-standing CNV (12 months or more), preoperative visual acuity (VA) 0.16 (mean); category II, CNV (duration < 12 months), preoperative VA 0.25 (mean). Evaluation protocol included the Early Treatment Diabetic Retinopathy Study (ETDRS) VA, clinical ophthalmological examination, fluorescein angiography and optical coherence tomography (OCT). Intravitreal injections of bevacizumab (Avastin) (IVB), 1.25 mg (0.05 ml), were given under an operating microscope and aseptic conditions in a theatre for surgery with intervals of 4 or 6 weeks during the first 3 months and subsequently according to clinical assessment. The follow-up was 6 months in all cases. RESULTS: At 6 months, mean VA had improved by 4.6 ETDRS letters in the entire case material (P = 0.001), by 3.9 letters in category I (duration 12 months or more) and by 6.0 letters in category II (duration < 12 months). A total of 148 IVB (mean 4.1 injections/eye) were delivered during 6 months, the first 3 months comprising 3.1 IVB (mean) and the last 3 months 1.0 IVB (mean). No eyes suffered visual decline of 15 ETDRS letters. Fluorescein angiograms displayed stabilization or regression of CNV activity; OCT showed resorption of intraretinal oedema and subretinal fluid. No severe complications occurred but recurrence was common, and repeated IVBs were necessary in most cases during the 6-month period. CONCLUSION: When addressing the issue of frequency of IBV, we observed that 6-week intervals were sufficient because VA and CNV lesions generally stabilized at 4 weeks. The gain in VA was promising in eyes with < 12 months CNV duration. Even in eyes with a longer CNV duration, a slight visual improvement was observed when retinal oedema resorbed, although subretinal fibrosis and general cellular damage certainly limited recovery.

Odergren A, Ming Y, Kvanta A. · Department of Clinical Neuroscience, Section of Ophthalmology and Vision, Karolinska Institutet, St. Eriks Eye Hospital, Stockholm, Sweden. · Curr Eye Res. · Pubmed #16966149 No free full text.

Abstract: PURPOSE: To evaluate the qualitative and quantitative effects of verteporfin photodynamic therapy (PDT) on laser-induced choroidal neovascularization (CNV) in the mouse. METHODS: PDT was applied to the normal mouse fundus using light doses of 32, 64, and 83 s, and histological analysis of the treated areas was performed. CNV was induced using krypton laser photocoagulation of the fundus, and the CNV lesions were subsequently treated with PDT using light doses of 32, 64, and 83 s. Enucleated eyes were analyzed with light and transmission electron microscopies, and measurements of CNV size were done on histologic sections and on isolectin B4-stained choroidal flat mounts. RESULTS: PDT induced a light dose-dependent damage to the surrounding neural retina in normal eyes. At a light dose of 32 s, minimal damage was detected in the neural retina, whereas higher light doses caused distortion and disruption of the outer and inner nuclear layers and of the retinal pigment epithelium. When PDT was applied over laser-induced CNV lesions, the relative height of the lesions was significantly reduced (p < 0.05) using all light doses. Transmission electron microscopy 1 day after PDT treatment revealed occlusion of many of the CNV vessels. One week after PDT treatment, the CNV lesions contained patent vessels irrespective of light dose applied. Accordingly, PDT treatment inhibited (p < 0.05) but did not halt CNV lesion growth. CONCLUSIONS: PDT treatment of laser-induced CNV may create an acute occlusion of neovessels and an inhibition of CNV lesion growth without apparent injury to the surrounding neural retina. However, PDT-treated areas will remain vascularized with continued growth of the CNV lesion, which in turn may explain the often limited effect of PDT in patients with neovascular age-related macular degeneration. Elevating the PDT light dose will not increase the treatment effect substantially but may lead to increased collateral injury.

Ming Y, Algvere PV, Odergren A, Berglin L, van der Ploeg I, Seregard S, Kvanta A. · Department of Ophthalmology, St. Erik's Eye Hospital, Karolinska Institutet, Stockholm, Sweden. · Invest Ophthalmol Vis Sci. · Pubmed #15161865 links to  free full text

Abstract: PURPOSE: Transpupillary thermotherapy (TTT) is currently being evaluated for treatment of choroidal neovascularization (CNV) in age-related macular degeneration. To optimize TTT for CNV, the effect was analyzed of invisible (subthreshold) or visible (threshold) doses of TTT on the normal mouse retina and on experimental CNV. METHODS: TTT was delivered to the normal retina of 42 mice with a diode laser at increasing power settings (50, 60, 70, or 80 mW), to obtain thermal lesions ranging from invisible (subthreshold) to visible (threshold) burns. CNV was induced in 53 mice by krypton laser photocoagulation of the fundus, after which the CNV lesions were treated with TTT (50, 60, or 80 mW). Eyes were enucleated 7 days after TTT and prepared for histology, and the CNV complex was evaluated on hematoxylin-eosin stained serial sections by measuring the maximum height of the CNV lesions. Ultrastructural changes were examined by transmission electron microscopy. RESULTS: Increasing the TTT laser power yielded gradually more visible effects. At 50 mW, which induced subthreshold burns, no damage was seen in the neural retina, retinal pigment epithelium (RPE), or choroid at any time point. By contrast, eyes treated with higher power exhibited progressively more damage to the neural retina, including a complete disruption of the outer nuclear layer. When TTT was applied to the laser-induced CNV lesions, the height of lesions was significantly reduced (P < 0.001) in response to all three power settings at 7 days after treatment. The mean relative thickness of the CNV lesion was 3.29 +/- 0.89 in untreated mice, whereas in TTT-treated mice it was 1.69 +/- 0.35, 1.69 +/- 0.41 and 1.70 +/- 0.17 at power settings of 50, 60, and 80 mW, respectively. The overlying neural retina showed no apparent damage with the 50- or 60-mW settings, whereas outer nuclear layer disruption occurred with a power of 80 mW. Electron microscopy confirmed the presence of vascular occlusion at 1 day and a fibrotic scar at 7 days after TTT. CONCLUSIONS: Subthreshold TTT can effectively occlude newly formed vessels and cause regression of the experimental CNV complex without damaging the neural retina. The results demonstrate the importance of using subthreshold laser power in experimental and clinical evaluation of TTT.

Chong NH, Kvanta A, Seregard S, Bird AC, Luthert PJ, Steen B. · Department of Ophthalmology, King's College Hospital, London, United Kingdom. · Am J Ophthalmol. · Pubmed #14597066 No free full text.

Abstract: PURPOSE: To assess the expression of MMP (matrix metalloproteinase)-2 and -9 and TIMP (tissue inhibitors of metalloproteinases)-1, -2, and -3 in Sorsby fundus dystrophy. DESIGN: Cliniciopathological report. METHODS: A donor eye with a confirmed S181C mutation in the TIMP-3 gene and an age-matched normal donor eye were studied using in situ hybridization technique with MMP -2 and -9 and TIMP -1, -2, and -3 probes. RESULTS: There is a reduction of mRNA expression of MMP-2 and TIMP-3 in the Sorsby retinal pigment epithelium cells. CONCLUSIONS: Increased expression of TIMP-3 mRNA does not cause accumulation of TIMP-3 in the Bruch membrane of Sorsby fundus dystrophy nor is it likely to cause age-related macular degeneration.

Berglin L, Sarman S, van der Ploeg I, Steen B, Ming Y, Itohara S, Seregard S, Kvanta A. · Department of Ophthalmology, Karolinska Institute, Stockholm, Sweden. · Invest Ophthalmol Vis Sci. · Pubmed #12506102 links to  free full text

Abstract: PURPOSE: Findings in studies have suggested a role for matrix metalloproteinase (MMP)-2 in angiogenesis, including choroidal neovascularization (CNV). To investigate further, the current study was conducted to observe the formation of experimental CNV in MMP-2-deficient mice. METHODS: CNV was induced in wild-type and MMP-2-deficient mice by krypton laser photocoagulation of the fundus. The time-course of expression of MMP-2 mRNA after laser treatment was determined by in situ hybridization with anti-sense and sense cRNA probes. MMP-2 protein distribution was determined by immunohistochemistry. Ten days after treatment, the extent of CNV was evaluated on hematoxylin-eosin stained serial sections. The maximum height of the CNV lesions was calculated by image analysis of digitized histologic images. RESULTS: Expression of MMP-2 mRNA was detected in the CNV lesions at day 3 after laser treatment and peaked at day 5, after which it slowly declined. MMP-2 mRNA expression appeared to be highest at the margins of the membrane. Immunostaining for MMP-2 confirmed the presence of MMP-2 protein in the CNV lesions. The CNV lesions of MMP-2-deficient mice showed that relative thickness was reduced by 31% compared with wild-type mice (P = 0.006). CONCLUSIONS: The present study demonstrated that MMP-2 mRNA and protein are upregulated during experimental CNV in the mouse. The marked difference in thickness of the CNV membrane between wild-type and MMP-2-deficient mice shows that MMP-2 is involved in the formation of experimental CNV in the mouse. These results suggest that pharmacologic targeting of MMPs, including MMP-2, may reduce formation of CNV in conditions such as age-related macular degeneration.

Berglin L, Algvere P, Olivestedt G, Crafoord S, Stenkula S, Hansson LJ, Tomic Z, Kvanta A, Seregard S. · Department of Retina and Oncology, St. Eriks Eye Hospital, Polhemsgatan 50, S-112 82 Stockholm, Sweden. · Acta Ophthalmol Scand. · Pubmed #11782223 No free full text.

Abstract: PURPOSE: To compare the visual outcome after surgical removal of subfoveal choroidal neovascularization (CNV) in patients younger and older than 50 years of age. METHODS: Patient records from all Swedish centers performing submacular CNV surgery were reviewed and 90 patients treated between 1992-1999 with a follow-up of 6 months or more were included. The results obtained in 49 patients aged 51-89 years (median=72 years) with neovascular disease caused by age-related macular degeneration (AMD) were compared with the outcome of 41 patients aged 6-49 years (median=36 years) with CNV secondary to non-AMD causes. The main outcome measure was the improvement or deterioration in visual acuity (standardized in logMAR units) at 6 months following surgery. Secondary endpoints were recurrent CNV and surgical complications. RESULTS: The level of preoperative visual acuity was not significantly different between younger patients with CNV associated with non-AMD and older patients with visual loss due to AMD (p=0.069). However, visual acuity at 6 months after surgery was better (p=0.0042) in younger patients (median improvement=0.19 logMAR) than in older patients (median improvement=0.0 log MAR). Marked visual improvement (>1 log MAR unit) was seen in 29% of non-AMD patients <50 years compared to 0% in the AMD group >50 years. CONCLUSION: Surgical removal of submacular CNV does not appear to improve visual acuity in patients > 50 years of age. However, it may be beneficial for younger patients where a substantial improvement of visual acuity is seen in a subset of these patients. Further studies are required to assess the long-term outcome.

Kvanta A, Shen WY, Sarman S, Seregard S, Steen B, Rakoczy E. · Department of Ophthalmology, St. Erik's Eye Hospital, Karolinska Institutet, Stockholm, Sweden. · Curr Eye Res. · Pubmed #11120556 No free full text.

Abstract: PURPOSE: Matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade basement membrane and extracellular matrix proteins. To gain information on the possible role of MMPs in choroidal neovascularization (CNV), we have analyzed the mRNA expression of MMP-2 and MMP-9, two forms of MMPs implicated in ocular neovascularization, in a rat model. METHODS: Choroidal neovascularization was induced in pigmented rats by krypton laser photocoagulation of the fundus whereafter eyes were enucleated at 1, 3, 5, 7, 10 and 60 days. Antisense and sense riboprobes were generated using DNA complementary to MMP-2 and MMP-9, and mRNA expression was analyzed using in situ hybridization. RESULTS: In the untreated eyes MMP-2 mRNA expression was weakly detected in cells within the choroid. In laser-treated eyes MMP-2 mRNA expression was markedly increased and mainly localized to macrophage-like and retinal pigment epithelial (RPE)-like cells invading the choroid, subretinal space and inner retina. This increase in MMP-2 mRNA expression peaked at day 10 whereafter a decline was detected. MMP-9 mRNA expression was low in untreated eyes and did not increase following laser treatment. CONCLUSION: The results show that MMP-2 mRNA expression is increased in experimental CNV, and support of a role for MMP-2 in the development of CNV in age-related macular degeneration.