Macular Degeneration: Ogura Y

Yasukawa T, Ogura Y, Sakurai E, Tabata Y, Kimura H. · Kurashiki Central Hospital, Kurashiki 710-8602, Japan; Department of Ophthalmology, Nagoya City University Medical School, Aichi 467-8601, Japan. · Adv Drug Deliv Rev. · Pubmed #16263193 No free full text.

Abstract: Vitreoretinal diseases involving age-related macular degeneration (AMD) are refractory to most topical or systemic drugs. The retina and the vitreous cavity have a unique position regarding pharmacokinetics in that the inner and outer blood retinal barriers separate the retina and vitreous from the systemic circulation. Eye drops achieve minimal therapeutic concentrations in the vitreoretinal tissue. Drug delivery systems are a strategy to address this. Intraocular sustained drug release using implantable devices has been investigated to treat vitreoretinal diseases. Possible targeted diseases include those in which repeated intraocular injections are effective (cytomegalovirus retinitis, uveitis), diseases requiring surgery (proliferative vitreoretinopathy), and chronic diseases (AMD, macular edema, retinitis pigmentosa). Hydrophobic or hydrophilic polymers shaped into a sheet, disc, rod, plug, or a larger device can be implanted into the subretinal space, intrascleral space, vitreous space, peribulbar space, or at the pars plana. Many researchers suggest the feasibility of these implants to treat AMD.

Kimura H, Yasukawa T, Tabata Y, Ogura Y. · Department of Ophthalmology, Nagoya City University Medical School, Mizuho-ku, Nagoya, 4678601, Aichi, Japan. · Adv Drug Deliv Rev. · Pubmed #11672877 No free full text.

Abstract: Subfoveal choroidal neovascularization (CNV) causes significant visual loss, especially in patients with age-related macular degeneration (AMD). Several pharmaceutical treatments that use anti-angiogenic agents have been tried to inhibit the activity of CNV experimentally and clinically. In general, however, systemically administered drugs may reach not only targeted tissues but also other tissues, resulting in unwanted side effects. Also, to maintain therapeutic levels of the drugs in targeted tissues, frequent administration for an extended period of time is required. To solve these problems, drug delivery systems targeted to the CNV are being developed. Anatomic characteristics of CNV tissues resemble those of tumor vasculature, exhibiting enhanced permeability and retention effect. Drug targeting to CNV may be feasible in the same manner as it is to tumors. In this review, we describe two approaches of drug targeting to CNV: passive targeting and active targeting.

Yuzawa M, Yoneya S, Uyama M, Takahashi K, Takeda M, Shiraga F, Miki T, Shiraki K, Hayashi K, Ogura Y, Komemushi S, Matsui M. · Department of Ophthalmology, Surugadai Hospital of Nihon University, 1-8-13 Surugadai, Kanda, Chiyoda-ku, Tokyo 101-8309, Japan. · Nippon Ganka Gakkai Zasshi. · Pubmed #11915378 No free full text.

Abstract: PURPOSE: To evaluate the proper clinical dosage of indocyanine green(ICG) in angiography for detecting choroidal neovascularization(CNV) of exudative age-related macular degeneration(AMD). SUBJECTS AND METHODS: Indocyanine green angiography (IA) was performed using a randomized crossover method with two different doses on two occasions. Ease of detection, side effects and clinical serum data were also evaluated. RESULTS: Among the 39 eyes, detection of CNV using 12.5 mg and 25 mg was most effective in 21 and 31 eyes respectively, showing a statistically significant difference. Slight vomiting was observed temporarily in one patient who had taken 25 mg. CONCLUSION: A dose of 25 mg is appropriate for detection of CNV of exudative AMD and this dosage raises no safety concerns.

Takeda A, Baffi JZ, Kleinman ME, Cho WG, Nozaki M, Yamada K, Kaneko H, Albuquerque RJ, Dridi S, Saito K, Raisler BJ, Budd SJ, Geisen P, Munitz A, Ambati BK, Green MG, Ishibashi T, Wright JD, Humbles AA, Gerard CJ, Ogura Y, Pan Y, Smith JR, Grisanti S, Hartnett ME, Rothenberg ME, Ambati J. · Department of Ophthalmology & Visual Science, University of Kentucky, Lexington, Kentucky 40506, USA. · Nature. · Pubmed #19525930 No free full text.

Abstract: Age-related macular degeneration (AMD), a leading cause of blindness worldwide, is as prevalent as cancer in industrialized nations. Most blindness in AMD results from invasion of the retina by choroidal neovascularisation (CNV). Here we show that the eosinophil/mast cell chemokine receptor CCR3 is specifically expressed in choroidal neovascular endothelial cells in humans with AMD, and that despite the expression of its ligands eotaxin-1, -2 and -3, neither eosinophils nor mast cells are present in human CNV. Genetic or pharmacological targeting of CCR3 or eotaxins inhibited injury-induced CNV in mice. CNV suppression by CCR3 blockade was due to direct inhibition of endothelial cell proliferation, and was uncoupled from inflammation because it occurred in mice lacking eosinophils or mast cells, and was independent of macrophage and neutrophil recruitment. CCR3 blockade was more effective at reducing CNV than vascular endothelial growth factor A (VEGF-A) neutralization, which is in clinical use at present, and, unlike VEGF-A blockade, is not toxic to the mouse retina. In vivo imaging with CCR3-targeting quantum dots located spontaneous CNV invisible to standard fluorescein angiography in mice before retinal invasion. CCR3 targeting might reduce vision loss due to AMD through early detection and therapeutic angioinhibition.

Hirata M, Yasukawa T, Wiedemann P, Kimura E, Kunou N, Eichler W, Takase A, Sato R, Ogura Y. · Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya-shi, Aichi, Japan. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #19330346 No free full text.

Abstract: PURPOSE: Abnormal fundus autofluorescence (FAF) is associated with the incidence or progression of dry and wet age-related macular degeneration (AMD). We previously developed a rabbit AMD model with drusen and type-1 choroidal neovascularization (CNV) that mimics the accumulation of lipofuscin using artificial glycoxidized particles. The objective of the current study was to investigate in vitro effects of glycoxidized particles on retinal pigment epithelial (RPE) cells, and the FAF and fate of injected particles in this model. METHODS: Glycoxidized particles were prepared by a 4-day incubation of water-in-oil emulsions of serum albumin and glycolaldehyde to allow glycoxidation and consequent cross-linking. After particles were added in the culture medium of confluent human RPE cells, cell viability, adhesion activity, and proliferation activity were assessed by cell counting. In anesthetized rabbits, 250 microg of glycoxidized particles were injected into the subretinal space to induce experimental AMD. FAF measurement and angiography with sodium fluorescein and indocyanine green were performed periodically using the Heidelberg Retina Angiograph 2 (HRA2). The eyes enucleated, and the lung and the spleen, excised at week 4 or 12, were histologically evaluated by light and fluorescence microscopy. RESULTS: Glycoxidized particles phagocytosed did not impair the cell viability, adhesion, and proliferation of RPE cells, as compared with RPE cells in controls. HRA2 showed different patterns of abnormal FAF in the area with the implanted glycoxidized particles, similar to pathological FAF patterns in aging human eyes with or without AMD. Histologic examination showed accumulated glycoxidized particles and large lipofuscin granules with green autofluorescence in and under the RPE and at the margins of or beneath drusen, possibly associated with abnormal FAF. In addition, some particles were detected in the lung and the spleen. CONCLUSIONS: Glycoxidized particles phagocytosed might stay in RPE cells without any acute biological reaction. Our rabbit model of AMD simulated abnormal FAF patterns observed in aging human eyes with or without AMD. Glycoxidized particles phagocytosed by RPE cells could be deposited on Bruch's membrane in rabbits, possibly excreted in part into choroidal circulation. This model may be useful for understanding various patterns of abnormal FAF histologically, and for elucidating the pathogenesis of AMD.

Mizuno D, Matsubara A, Ogura Y. · Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, 1-Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #18436845 links to  free full text

Abstract: PURPOSE: Macular edema is one of the serious side effects associated with panretinal photocoagulation (PRP). The inhibitory effect of triamcinolone acetonide (TA) on leukocyte-endothelial cell interactions in vivo after PRP was evaluated. METHODS: Argon laser photocoagulation was performed in one half of the retinas in male Brown Norway rats. Experimental rats were injected with 2 mg TA (50-microL volume) in the posterior sub-Tenon space, and the vehicle-treated rats were injected with the same amount of saline (50 microL) immediately after PRP. Untreated rats were used as the control. Leukocyte dynamics in retinal microcirculation and retinal vessel diameters were evaluated 1 day after laser photocoagulation with the use of acridine orange digital fluorography. Retinal thickness was evaluated with optical coherence tomography. RESULTS: The number of rolling leukocytes and accumulating leukocytes in the retina decreased by 66% in the TA-treated rats (P < 0.01) and by 24% (P < 0.05), respectively, compared with the number in the vehicle-treated rats. Retinal thickness in the vehicle-treated rats was significantly thicker than that in control rats 1 day after laser photocoagulation (P < 0.01). Retinal thickness in the TA-treated rats was significantly suppressed compared with that in the vehicle-treated rats (P < 0.05). CONCLUSIONS: Sub-Tenon administration of TA significantly suppressed leukocyte dynamics in rat retinal microcirculation and decreased retinal edema after laser photocoagulation. The results suggest that the suppression of leukocyte-endothelial cell interactions in retinal microcirculation may be one mechanism responsible for the therapeutic effect of sub-Tenon TA on postlaser retinal edema.

Matsubara A, Nakazawa T, Noda K, She H, Connolly E, Young TA, Ogura Y, Gragoudas ES, Miller JW. · Angiogenesis and Laser Laboratories, Retina Service, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA. · Invest Ophthalmol Vis Sci. · Pubmed #17898299 links to  free full text

Abstract: PURPOSE: To investigate the mechanism of cell death in laser-induced choroidal neovascularization (CNV) after photodynamic therapy (PDT). METHODS: PDT was performed in Brown-Norway rats using laser light at a wavelength of 689 nm, irradiance of 600 mW/cm(2), and fluence of 25 J/cm(2) after intravenous injection of verteporfin at the doses of 3, 6, and 12 mg/m(2). Apoptotic cells in CNV were detected by TUNEL assay at 1, 3, 6, 15, 24, and 48 hours after PDT. Caspase activation at 1, 3, 6, 15, and 24 hours after PDT was determined by immunohistochemistry (IHC) with a cleaved caspase-3 or -9 antibody. Akt activity was determined by Western blot and IHC with a phosphorylated-Akt (pAkt) antibody. To investigate the roles of Akt in PDT-induced apoptosis, insulin-like growth factor (IGF)-1, an Akt activator, with or without wortmannin, an inhibitor of PI3K-Akt pathway, was injected into the vitreous before PDT. RESULTS: The number of TUNEL-positive cells in CNV increased at 3 hours after PDT and peaked at 6 hours, showing a dose dependence of verteporfin. Caspase activation was detected in TUNEL-positive cells. Dephosphorylation of Akt in CNV occurred within 1 hour. IGF-1 significantly activated Akt and suppressed the number of TUNEL-positive cells in CNV, and the effects of IGF-1 were diminished by wortmannin. CONCLUSIONS: PDT induced caspase-dependent apoptosis in CNV. These results suggest that PDT leads to dephosphorylation of Akt and subsequent activation of the caspase-dependent pathway. Understanding the intracellular signaling mechanisms of apoptosis in PDT may lead to more selective and effective treatment of CNV secondary to age-related macular degeneration.

Hirano Y, Sakurai E, Yoshida M, Ogura Y. · Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. · Ophthalmic Res. · Pubmed #17596753 No free full text.

Abstract: AIMS: To compare the efficacy ofa combination therapy of triamcinolone acetonide (TA) administration with and without vitrectomy in eyes with macular edema associated with branch retinal vein occlusion over a 1-year period. METHODS: A retrospective, case-control study was conducted in 15 eyes of 15 patients with macular edema associated with branch retinal vein occlusion. Eight eyes underwent simultaneous intravitreal and posterior sub-Tenon capsule injections of TA (TA-injected group). Seven eyes underwent vitrectomy with intravitreal or simultaneous posterior sub-Tenon capsule injection of TA (vitrectomy with TA group). Macular thickness and visual acuity were measured before and at 1, 3, 6 and 12 months after the therapy. RESULTS: Twelve months after the therapy, mean visual acuity improved significantly from baseline in both the TA-injected (p = 0.0069) and vitrectomy with TA groups (p = 0.0145). Macular thickness also improved significantly in both the TA-injected (p = 0.0065) and vitrectomy with TA groups (p = 0.0058). At 12 months after the therapy, there was no significant difference in visual acuity and macular thickness between the two groups (p = 0.3308 and 0.3711, respectively). At the early postoperative stage (1 and 3 months after the therapy), the central macular thickness in the TA-injected group was significantly less than that in the vitrectomy with TA group (p = 0.0140 and 0.0275, respectively); there was no significant difference in visual acuity between the two groups (p = 0.0796 and 0.3753, respectively). CONCLUSION: TA injection without vitrectomy was as effective as a combination therapy of TA injection with vitrectomy.

Mizuno S, Nishiwaki A, Morita H, Miyake T, Ogura Y. · Department of Ophthalmology and Visual Sciences, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #17525219 links to  free full text

Abstract: PURPOSE: Recent studies have reported that intravitreal or posterior sub-Tenon's injection of triamcinolone acetonide (TA) is effective in the treatment of macular edema resulting from retinal microcirculatory disturbances such as diabetic retinopathy and retinal vein occlusion. The effects of periocular administration of TA on leukocyte-endothelium interactions were studied after transient retinal ischemia. METHODS: Transient retinal ischemia was induced by temporary ligation of the optic nerve sheath for 60 minutes in male Long-Evans rats. After the induction of ischemia, experimental eyes received a periocular injection of TA (2 mg). In control animals, the same volume of saline was administered. Leukocyte dynamics were evaluated in the retinal microcirculation using acridine orange digital fluorography. Also, retinal thickness was studied by using optical coherence tomography and a histologic METHOD: The retinal mRNA expression of P-selectin and intercellular adhesion molecule (ICAM)-1 was semiquantitatively studied with RT-PCR. RESULTS: The leukocytes rolling along retinal vein linings increased after ischemia in the vehicle-treated rats (32.5 +/- 2.1 cells/min). No rolling leukocytes, however, were seen in the TA-treated rats. The number of accumulated leukocytes was significantly lower in the TA-treated rats (831 +/- 99 cells/mm2) than in the control (971 +/- 81 cells/mm2, P < 0.05). The treatment decreased the retinal thickness and the mRNA expression of P-selectin and ICAM-1. CONCLUSIONS: The present study demonstrated that the periocular injection of TA effectively decreased retinal thickness and inhibited leukocyte-endothelium interactions in the retina after ischemia. Downregulation of adhesion molecules of retinal vascular endothelium induced by TA may play a role in the course.

Yasukawa T, Wiedemann P, Hoffmann S, Kacza J, Eichler W, Wang YS, Nishiwaki A, Seeger J, Ogura Y. · Department of Ophthalmology and Eye Clinic, University of Leipzig Medical Faculty, Leipzig, Germany. · Graefes Arch Clin Exp Ophthalmol. · Pubmed #17406884 No free full text.

Abstract: PURPOSE: The biogenesis of drusen, a hallmark of age-related macular degeneration (AMD), is still unclear. Lipofuscin, which extensively accumulates with age in RPE cells, is hardly soluble, derived in part from oxidation byproducts of the photoreceptor outer segments. The purpose of the current study is to develop a new AMD model in rabbits using glycoxidized particles as imitation lipofuscin, and determine whether accumulation of lipofuscin as insoluble material may play a role in drusen biogenesis and other pathogenesis of AMD. METHODS: To mimic the accumulation of insoluble lipofuscin, glycoxidized microspheres (glycox-MS) were made through a glycoxidation process with albumin and glycolaldehyde, alpha-hydroxy aldehyde. As a control, microspheres made with glutaraldehyde (cMS) and soluble glycoxidized (glycox-) albumin were prepared. Each material was implanted into the subretinal space in rabbits. The implanted area was assessed by funduscopy, fluorescein angiography, histology, and transmission electron microscopy (TEM). RESULTS: Compared with control microspheres, glycox-MS stagnated for a prolonged period in the cytoplasm of RPE cells. Eyes implanted with glycox-MS produced drusen-like deposits at a significantly higher frequency, when compared with the controls. Glycox-MS were observed at the margin of or beneath the drusen-like deposits in all cases. In some eyes with glycox-MS, late-onset sub-RPE choroidal neovascularization was observed, while control groups did not have these findings. CONCLUSIONS: These results suggest that the accumulation of indigestible granules such as lipofuscin in RPE or subsequent depositions toward Bruch's membrane may play a role in drusen biogenesis as a trigger of inflammation or via other mechanisms. This model of AMD may be useful to elucidate drusen biogenesis and pathogenesis of AMD.

Ashikari M, Ozeki H, Tomida K, Sakurai E, Tamai K, Ogura Y. · Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Science, Nagoya, Japan. · Jpn J Ophthalmol. · Pubmed #16897220 No free full text.

Abstract: PURPOSE: To evaluate dye retention in the fundus after indocyanine green (ICG)-assisted internal limiting membrane peeling. METHODS: Ten eyes with stage 3 or 4 nondiabetic idiopathic macular hole (MH group) and six eyes with diffuse diabetic macular edema (DM group) were studied. The fundus was examined with 780-nm infrared illumination by a scanning laser ophthalmoscope (SLO) after ICG-assisted internal limiting membrane peeling. The postoperative follow-up period ranged from 6 to 12 months (mean+/-SD, 3.7+/-2.6 months). RESULTS: Fluorescence from ICG was detected in all studied eyes in both groups up to 6 months after surgery. At 9 months after surgery, ICG fluorescence was visible in all eyes of the DM group, but in only one-third of eyes of the MH group. No fluorescence was detected in fellow eyes that had not been operated on. CONCLUSION: The present study using SLO revealed that ICG remains in the fundus for over 6 months after surgery. The results also suggested that a longer time might be required for dye clearance from the diabetic retina than from the nondiabetic retina.

Ito T, Nozaki M, Ogura Y. · Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Japan. · Nippon Ganka Gakkai Zasshi. · Pubmed #16764319 No free full text.

Abstract: PURPOSE: We investigated the incidence and risk factors of intraocular pressure (IOP) elevation following triamcinolone administration for macular disorders. METHODS: Intravitreal or posterior sub-Tenon's injections of triamcinolone acetonide were conducted on 119 eyes with macular disorders. The change in IOP was followed for all cases. Risk factors for IOP elevation were examined regarding causal disease, history of vitrectomy, methods of injection, frequency of injection, refractive power, and age. RESULT: The difference between the mean baseline IOP (13.0 +/- 2.9 mmHg) and the maximum mean IOP (21.5 +/- 9.8 mmHg) was statistically significant (p< 0.0001). The final mean IOP was 15.1 +/- 3.6 mmHg. Forty-one eyes (34.5%) had IOP elevation over 21 mmHg during the follow-up. Fifty-nine eyes (49.6%) showed pressure elevation of over 5 mmHg. One eye (1%) required trabeculotomy to control the IOP. Risk factors for the IOP elevation included younger age, high myopia, no history of vitrectomy, and multiple injections. CONCLUSION: Careful follow-up of the IOP is required after triamcinolone acetonide injections.

Matsunaga N, Ozeki H, Hirabayashi Y, Shimada S, Ogura Y. · Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Japan. · Retina. · Pubmed #15805908 No free full text.

Abstract: PURPOSE: To histopathologically evaluate the internal limiting membrane (ILM) in diabetic eyes with macular edema as compared to nondiabetic controls. METHODS: The authors ultrastructurally and immunohistochemically studied ILM specimens that were intentionally peeled from five eyes with diabetic maculopathy, comprising four with diffuse diabetic macular edema and one with macular hole accompanying diabetic retinopathy (DM group), and five with nondiabetic idiopathic macular hole (MH group). They compared ultrastructural and immunohistochemical findings between the two groups. RESULTS: A larger amount of cellular elements was observed on the vitreous side of the ILM in the DM group. The thickness of the ILM in the DM group was significantly increased (mean 4.8 +/- 1.6 microm) compared with that in the MH group (1.8 +/- 0.6 microm) (P < 0.0001). Immunoreactions for heparan sulfate proteoglycan in the ILM were more abundant in the DM group than in the MH group. CONCLUSION: The ILM thickening and cell abundance on the vitreous surface might contribute to the course and the pathogenesis of diabetic maculopathy.

Otani A, Takagi H, Oh H, Koyama S, Sugita G, Ogura Y. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Retina. · Pubmed #12824844 No free full text.

This publication has no abstract.

Otani A, Takagi H, Oh H, Koyama S, Ogura Y, Matumura M, Honda Y. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto 606, Japan. · Microvasc Res. · Pubmed #12074642 No free full text.

This publication has no abstract.

Nonaka A, Kiryu J, Tsujikawa A, Yamashiro K, Nishijima K, Kamizuru H, Ieki Y, Miyamoto K, Nishiwaki H, Honda Y, Ogura Y. · Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #11923267 links to  free full text

Abstract: PURPOSE: Macular edema is one of the most serious adverse effects after retinal scatter laser photocoagulation. It has been suggested that the changes in the distribution of retinal blood flow or the inflammatory reaction after photocoagulation may be involved in the pathogenesis of macular edema, but little information is available about its exact mechanism. This study was designed to evaluate quantitatively leukocyte-endothelial cell interactions and vascular permeability in the nonphotocoagulated portions of the retina after partial scatter laser photocoagulation. METHODS: Argon laser photocoagulation was performed in one half of the retina in male pigmented rats (n = 90). In the other half of the retina, leukocyte dynamics after photocoagulation were evaluated in vivo with acridine orange digital fluorography. Retinal vessel permeability was quantified by using Evans blue dye. RESULTS: Scatter laser photocoagulation caused significant inflammatory leukocyte-endothelial interactions not only in the photocoagulated but also in the untreated half of the retina. In the nonphotocoagulated half of the retina, the number of leukocytes rolling along the major retinal veins increased after photocoagulation and peaked at 12 hours (14.3 +/- 4.5 cells/min per vessel). Leukocyte accumulation in the untreated half of the retina increased after photocoagulation, with a peak of 47.5 +/- 13.0 cells/mm(2) 24 hours after photocoagulation. Retinal vascular permeability in the untreated half of the retina gradually increased after photocoagulation. CONCLUSIONS: Scatter laser photocoagulation increased leukocyte rolling and subsequent accumulation in both the photocoagulated and the untreated portions of the retina. The accumulated leukocytes may be involved in the augmented vascular permeability in the untreated retina, resulting in retinal edema after photocoagulation.

Yasukawa T, Kimura H, Tabata Y, Miyamoto H, Honda Y, Ikada Y, Ogura Y. · Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, Japan. · Curr Eye Res. · Pubmed #11262619 No free full text.

Abstract: PURPOSE: Active drug targeting with monoclonal antibody to neovascular vessels may be a potential treatment for choroidal neovascularization (CNV) in age-related macular degeneration (AMD). Endoglin (CD105) is a proliferating endothelial cell marker with excellent potential for targeting. The goals of this study were to investigate the expression of CD105 in CNV membranes surgically excised from patients with AMD and CNV lesions induced by intense laser photocoagulation in a cynomolgus monkey and to evaluate the in vitro effect of immunoconjugates on endothelial cells. METHODS: CNV membranes were surgically excised from 10 patients with AMD. Experimental CNV was induced by intense laser photocoagulation in a cynomolgus monkey. Immunolocalization of CD105 on frozen sections of CNV lesions was studied by immunohistochemical evaluation. Anti-von Willebrand's factor antibody was used as an endothelial cell marker. The cytotoxic effect of immunoconjugates of anti-CD105 monoclonal antibody and dextran binding mitomycin C on human umbilical vein endothelial cells (HUVECs) was evaluated in vitro. RESULTS: Endothelial cells demonstrated strong immunoreactivity of CD105 in all surgically excised CNV membranes. In the monkey eye, CD105-positive cells were detected only in CNV lesions but not in normal chorioretinal tissues. Immunoconjugates with anti-CD105 monoclonal antibody showed a specific inhibitory effect on proliferating HU-VECs. CONCLUSIONS: These results suggest that anti-CD105 monoclonal antibody-mediated drug targeting has a potential to treat CNV in AMD.

Mandai M, Takahashi M, Miyamoto H, Hiroshiba N, Kimura H, Ogura Y, Honda Y, Sasai K. · Departments of Ophthalmology and Visual Science, Kyoto University Graduate School of Medicine, Kyoto, Japan. · Jpn J Ophthalmol. · Pubmed #11033133 No free full text.

Abstract: PURPOSE: The purpose of this study was to investigate the long-term effect of low-dose radiation therapy on subfoveal choroidal neovascularization associated with age-related macular degeneration. METHODS: The clinical course and visual outcome were compared retrospectively among two treated groups and a control group; 15 patients (15 eyes) received 10 Gy, another 15 patients (15 eyes) received 20 Gy. The control group consisted of 15 patients (15 eyes) without treatment. All patients were followed up for at least 18 months, and most were followed up for 3 years. The macula was irradiated with either 10 Gy in 5 fractions or with 20 Gy in 10 fractions after computed tomography (CT) simulation enabled real-time treatment planning from multiple CT slices. RESULTS: During the 3 years of follow-up, the lesions became better in 5 eyes, unchanged in 1, and worse in 9 with 10 Gy radiation; better in 7 eyes, unchanged in 1, and worse in 7 eyes with 20 Gy; and better in 1 eye and worse in 14 with no treatment. The difference between the groups treated with radiation and the control was statistically significant (P <.05). Visual acuity was also significantly better in the group receiving 20 Gy than in the control group up to 2 years after radiation (P <.01). CONCLUSION: Radiation may extend the period of good visual function substantially by reducing subfoveal choroidal neovascularization activity.

Miyamoto H, Kimura H, Yasukawa T, Honda Y, Tabata Y, Ikada Y, Sasai K, Ogura Y. · Department of Ophthalmology and Visual Sciences, Graduate School of Medicine, Kyoto University, Japan. · Invest Ophthalmol Vis Sci. · Pubmed #10359332 links to  free full text

Abstract: PURPOSE: Radiation therapy has been used to treat choroidal neovascularization (CNV) in patients with age-related macular degeneration. The in vivo effect of applying focal x-ray irradiation to the eye of rabbits with experimental CNV was investigated. METHODS: CNV was induced in the rabbit eyes by subretinal implantation of gelatin hydrogel microspheres impregnated with basic fibroblast growth factor. Three weeks after implantation, 17 of 34 eyes with CNV lesions accompanied by fluorescein leakage were irradiated with a single dose of 20 Gy; the other 17 eyes were not irradiated and served as the controls. The eyes were examined before irradiation and 1, 2, and 4 weeks after irradiation, by indirect ophthalmoscopy and fluorescein angiography. The degree of a decreasing amount of fluorescein leakage from the CNV lesions after irradiation was graded using a computerized image analysis system and was compared in the irradiated and nonirradiated eyes. These eyes were also examined histologically and immunohistochemically. RESULTS: Fluorescein leakage from the CNV lesions had significantly decreased in the eyes irradiated with 20 Gy compared with the control eyes, throughout the study period (P < 0.05). Histologic and immunohistochemical studies at 4 weeks after irradiation demonstrated that the degree of vascular formation and the number of vascular endothelial cells in the subretinal membrane of the irradiated eyes were less than those of the control eyes. CONCLUSIONS: Focal x-ray irradiation at the ocular region effectively reduced experimental CNV activity. These results support the possibility that radiation therapy may be beneficial in treating CNV.

Kimura H, Spee C, Sakamoto T, Hinton DR, Ogura Y, Tabata Y, Ikada Y, Ryan SJ. · Doheny Eye Institute, University of Southern California School of Medicine, Los Angeles 90033, USA. · Invest Ophthalmol Vis Sci. · Pubmed #9950614 links to  free full text

Abstract: PURPOSE: To determine the sequence of cellular changes associated with a new rabbit model of subretinal neovascularization (SRN) induced by subretinal injection of basic fibroblast growth factor (bFGF)-impregnated microspheres. METHODS: bFGF-impregnated gelatin microspheres, prepared by forming a polyion complex between gelatin and bFGF, were subretinally implanted into rabbit eyes. The eyes were studied by immunochemistry at 3 days to 8 weeks after implantation. Antibodies to CD4, CD8, cytokeratin, CD31, glial fibrillary acidic protein (GFAP), and RAM11 were used. RESULTS: Cytokeratin-positive retinal pigment epithelial (RPE) cells appeared on day 3 and continued to increase in number in the subretinal space throughout the growth of the SRN membrane, becoming the predominant cell type. Macrophages (RAM11-positive) appeared early, but most disappeared within 7 days. GFAP-positive Müller cells were evident early in the retina but migrated into the subretinal space after 7 days; the gliotic adhesion they formed between the retina and the SRN membrane was prominent at 8 weeks. CD31-positive endothelial cells were first evident at 14 days and formed neovascular channels that were still present for up to 8 weeks. CD4- and CD8-positive lymphocytes appeared in the early stages but were few in number. CONCLUSIONS: SRN membranes are primarily composed of RPE cells and vascular endothelial cells. The membrane adheres to the retina by a gliotic band. The cellular components involved in the membrane of this model resemble those found in SRN membranes removed from patients with age-related macular degeneration.