Macular Degeneration: Del Priore LV

Shah AR, Del Priore LV. · Department of Ophthalmology, Columbia University, New York, New York, USA. · Curr Opin Ophthalmol. · Pubmed #19367162 No free full text.

Abstract: PURPOSE OF REVIEW: A careful analysis of randomized clinical trials on exudative age-related macular degeneration reveals apparent differences in behavior of untreated control eyes among these trials. A priori there are two possible explanations: each study contains a unique subpopulation of patients; or apparent differences arise from differences in time of entry of these eyes into clinical trials. RECENT FINDINGS: To correctly account for differences in time of entry into clinical trials, we introduced a horizontal translation factor, expressed in months, to shift each data subset horizontally to maximize r2 for the cumulative trend line; this increases the overall r2 to 0.95, demonstrating that most of the variation in visual acuity over time is explained by the initial visual acuity. This analysis also suggests that occult disease is an earlier stage than minimally classic and predominantly classic disease and that there is a subclinical stage of subfoveal exudation ('preoccult') for patients with age-related macular degeneration. SUMMARY: The pattern of vision loss experienced in age-related macular degeneration eyes with subfoveal choroidal neovascularization is uniform across a wide range of clinical trials, with apparent differences in initial and final visual acuity in untreated eyes arising from differences in the time of entry into clinical trials. Our data suggest that visual loss may occur during a preoccult phase of choroidal neovascularization, prior to the development of occult disease.

Del Priore LV, Tezel TH, Kaplan HJ. · Department of Ophthalmology, The Edward S. Harkness Eye Institute, Columbia University, NY, USA. · Prog Retin Eye Res. · Pubmed #17071125 No free full text.

Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness in the western world. Over the last decade, there have been significant advances in the management of exudative AMD with the introduction of anti-VEGF drugs; however, many patients with exudative AMD continue to lose vision and there are no effective treatments for advanced exudative AMD or geographic atrophy. Initial attempts at macular reconstruction using cellular transplantation have not been effective in reversing vision loss. Herein we discuss the current status of surgical attempts to reconstruct damaged subretinal anatomy in advanced AMD. We reinforce the concept of maculoplasty for advanced AMD, which is defined as reconstruction of macular anatomy in patients with advanced vision loss. Successful maculoplasty is a three-step process that includes replacing or repairing damaged cells (using transplantation, translocation or stimulation of autologous cell proliferation); immune suppression (if allografts are used to replace damaged cells); and reconstruction or replacement of Bruch's membrane (to restore the integrity of the substrate for proper cell attachment). In the current article we will review the rationale for maculoplasty in advanced AMD, and discuss the results of initial clinical attempts at macular reconstruction. We will then discuss the role of Bruch's membrane damage in limiting transplant survival and visual recovery, and discuss the effects of age-related changes within human Bruch's membrane on the initial attachment and subsequent proliferation of transplanted cells. We will discuss attempts to repair Bruch's membrane by coating with extracellular matrix ligands, anatomic reconstitution of the inner collagen layer, and the effects of Bruch's membrane reconstruction of ultrastuctural anatomy and subsequent cell behavior. Lastly, we will emphasize the importance of continued efforts required for successful maculoplasty.

Kaplan HJ, Tezel TH, Berger AS, Del Priore LV. · Department of Ophthalmology and Visual Sciences Washington University School of Medicine, St. Louis, Mo., USA. · Chem Immunol. · Pubmed #10590581 No free full text.

This publication has no abstract.

Sun K, Cai H, Tezel TH, Paik D, Gaillard ER, Del Priore LV. · Department of Ophthalmology, Harkness Eye Institute, Columbia University, New York, NY 10032, USA. · Mol Vis. · Pubmed #18199972 links to  free full text

Abstract: PURPOSE: We have shown previously that aging of human Bruch's membrane affects the attachment, survival and gene expression profile of the overlying retinal pigment epithelium (RPE). Herein we determine the effects of Bruch's membrane aging on RPE phagocytosis of rod outer segments. METHODS: Explants of human Bruch's membrane were prepared from cadaver donor eyes (aged 9-81years) within 48 h of death, and 6 mm punches were embedded with the basal lamina in a 96-well plate. Approximately 50,000 ARPE-19 cells per well were seeded onto the explant surface and cultured for two weeks until they reached confluence. In addition, ARPE-19 were also seeded onto RPE-derived extracellular matrix (RPE-ECM) that was unmodified or modified by nonenzymatic nitration. Bovine rod outer segments were purified by sucrose gradient centrifugation, labeled with 10 ug/ml fluorescein isothiocyanate, and added to ARPE-19 cultured on Bruch's membrane or RPE-ECM for 24 h. Phagocytic activity was quantified by flow cytometry of harvested cells. RESULTS: The ability of RPE to phagocytose rod outer segments decreased as a function of aging of Bruch's membrane; mean phagocytotic activity of ARPE-19 on younger Bruch's membrane was significantly higher than on older Bruch's membrane (129.7 +/- 34.8 versus 67.4 +/- 4.2 arbitrary units, respectively; p<0.01). Nitrite treatment of RPE-ECM decreased rod outer segment phagocytosis compared to untreated RPE-ECM and mimicked the effects of aging of human Bruch's membrane. CONCLUSIONS: Aging of human Bruch's membrane decreases rod outer segment phagocytosis by ARPE-19. This effect can be mimicked by nonenzymatic nitration of extracellular matrix in vitro. Our observations may have implications for understanding the role of aging changes within Bruch's membrane on pathogenesis of age-related macular degeneration and other disorders.

Tezel TH, Del Priore LV, Berger AS, Kaplan HJ. · Department of Ophthalmology & Visual Sciences, Kentucky Lions Eye Center, University of Louisville School of Medicine, Louisville, Kentucky, USA. · Am J Ophthalmol. · Pubmed #17303061 No free full text.

Abstract: PURPOSE: To improve visual function by retinal pigment epithelial (RPE) cell transplantation and systemic immunosuppression at the time of surgical removal of subfoveal choroidal neovascularization in exudative age-related macular degeneration (AMD). DESIGN: An interventional case series of RPE transplantation in exudative AMD. METHODS: Twelve patients (one eye only) underwent subfoveal membranectomy with transplantation of a sheet of adult human allogeneic RPE cells at a single institution and were followed for one year. Eligibility criteria included age >60, best-corrected acuity < or =20/63 and subfoveal neovascularization < or =9 disk areas on preoperative fluorescein angiography. All patients were started on triple immunosuppression postoperatively. The primary outcome measure was best-corrected vision, with contrast sensitivity and reading speed as secondary outcome measures. RESULTS: The best-corrected visual acuity (P = .085), contrast sensitivity (P = .204), and the reading speed (P = .077) did not change significantly at one year compared with preoperative values. Transplants showed no signs of rejection in patients who were able to continue the immunosuppressants for six months. Postoperative surgical complications included cataract progression requiring surgery (three of eight phakic eyes), retinal detachment (three eyes), intraoperative retinal breaks (two eyes), and macular pucker (two eyes). None of the patients developed cystoid macular edema on postoperative fluorescein angiography or postoperative inflammation. CONCLUSIONS: A sheet of adult human allogeneic RPE can be transplanted into the subretinal space in AMD patients at the time of subfoveal membranectomy. Systemic immune suppression appeared to prevent rejection of the transplanted tissue, but did not lead to an improvement in visual function.

Shah AR, Del Priore LV. · Department of Ophthalmology, Columbia University, 635 West 165th Street, New York, NY 10032, USA. · Am J Ophthalmol. · Pubmed #17188044 No free full text.

Abstract: PURPOSE: To analyze the randomized clinical trials in exudative age-related macular degeneration (AMD) to reveal apparent differences in the behavior of untreated control eyes among these trials. Herein we test the hypothesis that the behavior of untreated control eyes is actually the same in all studies, with apparent differences arising from differences in the time of entry of eyes into clinical trials. DESIGN: Retrospective meta-analysis of prior clinical trials. METHODS: Control eye data from six AMD studies (Macular Photocoagulation Study, Subfoveal Surgery Trial, Photodynamic Therapy [TAP] With Visudyne, pegaptanib trial for neovascular AMD, anecortave acetate trial, and 360 degree Macular Translocation Study) were plotted on a double reciprocal plot of 1/(Letters Lost) vs 1/(Months After Enrollment). To account for differences in time of entry into clinical trials, we introduced a horizontal translation factor to shift each data subset horizontally to maximize r(2) for the cumulative trend line. RESULTS: Cumulative data for untreated control eyes fits a straight line on a double reciprocal plot (r(2) = .9521); an untreated eye would eventually deteriorate to a final vision of 20/640. The slope of the line predicts that patients would experience half of the maximum final vision within 10.88 months after exudation onset. CONCLUSIONS: The pattern of vision loss experienced in AMD eyes with subfoveal neovascularization is uniform across a wide range of clinical trials, with apparent differences arising from differences in the time of entry of patients into clinical trials.

Cai H, Shin MC, Tezel TH, Kaplan HJ, Del Priore LV. · Department of Ophthalmology, Harkness Eye Institute, Columbia University, 635 W. 165th Street, New York, NY 10032, USA. · Arch Ophthalmol. · Pubmed #16966623 links to  free full text

Abstract: OBJECTIVE: To determine the gene expression profiles of primary retinal pigment epithelium (RPE) and iris pigment epithelium (IPE) using microarrays. METHODS: Primary RPE and IPE from 6 human donor eyes were collected, and total RNA was isolated. Differences in gene expression were determined using a human genechip (human U95Av2 [12 600 probes]; Affymetrix Inc, Santa Clara, Calif). RESULTS: Hierarchical cluster analysis differentiated the gene expression profiles of RPE and IPE clusters into 2 distinct groups. A mean +/- SD of 5308 +/- 416 gene probes were expressed in RPE vs 6130 +/- 205 in IPE. Sixty-eight genes were expressed only in RPE; 154 genes were expressed only in IPE. Twenty-two additional genes had greater than 3-fold increased expression in RPE vs IPE, and 147 genes had greater than 3-fold decreased expression in RPE vs IPE. CONCLUSION: There are major differences in the gene expression profiles of primary RPE vs IPE.Clinical Relevance The different gene expression profiles of primary RPE vs IPE harvested from the same donor eyes infer that it may be difficult for IPE to replace all aspects of damaged RPE function in transplantation studies.

Cai H, Del Priore LV. · Department of Ophthalmology, Harkness Eye Institute, Columbia University, New York, New York, USA. · Curr Eye Res. · Pubmed #16500769 No free full text.

Abstract: We investigated the effects of age-related changes within the Bruch membrane on the gene expression profile of the RPE. Immortalized human ARPE-19 cells were seeded onto acellular human Bruch membrane from younger and older donors and harvested 72 hr later; total RNA was isolated and the gene expression profile was determined using the Affymetrix Human Genome U95A gene chip. Twelve genes were upregulated and 8 genes were downregulated with Bruch membrane aging; RT-PCR confirms that Bruch membrane aging upregulates genes in RPE cells encoding for transforming growth factor alpha and downregulates genes for vitronectin and the membrane transporter ABCC5. The role of these changes in the pathogenesis of age-related diseases such as macular degeneration remains to be elucidated.

Cekiç O, Chang S, Tseng JJ, Barile GR, Del Priore LV, Weissman H, Schiff WM, Ober MD. · From the Department of Ophthalmology, College of Surgeons and Physicians of Columbia University, New York, New York 10032, USA. · Retina. · Pubmed #16205563 No free full text.

Abstract: PURPOSE: To evaluate the efficacy of intravitreal triamcinolone injection in eyes with macular edema due to branch retinal vein occlusion (BRVO) over a 2-year period. METHODS: The authors performed a retrospective chart review of 13 eyes of 13 patients (mean age 68 years) who underwent intravitreal injections with 4 mg triamcinolone acetonide for macular edema due to BRVO. Six eyes received a single injection. Repeated injections were performed in one eye twice, four eyes three times, and two eyes four times. Mean follow-up was 13 months (range, 4 to 24). The time between the onset of symptoms and the injection averaged 7.4 months (range, 2 to 24). RESULTS: Mean postinjection central foveal thickness decreased to 56% of preinjection values (529 mum versus 295 mum, P < 0 .001). Final visual acuity improved in seven eyes (range 2 to 6 Snellen lines), remained the same in four eyes (range 0 to 1 Snellen lines), and worsened in two eyes (range -1 to -4 Snellen lines) compared to baseline. The retinal thickness decreased in all cases; vision improved in most cases. As the number of injections increased cataractous changes increased. Visual acuity improvement was significantly correlated with patient age (P = 0.026). Eight patients developed steroid induced ocular hypertension controlled by topical medication. Cataract extraction was judged to aggravate macular edema in three of the five eyes undergoing surgery, based upon optical coherence tomography or fluorescein angiography. Median best postinjection visual acuity (20/50) was significantly better than that of baseline (20/100) (P = 0.028) as well as last follow-up (20/70) (P = 0.003). CONCLUSIONS: Intravitreal triamcinolone should be further evaluated as a treatment option for macular edema associated with BRVO.

Cekiç O, Chang S, Tseng JJ, Barile GR, Weissman H, Del Priore LV, Schiff WM, Weiss M, Klancnik JM. · Department of Ophthalmology, College of Surgeons and Physicians of Columbia University, Harkness Eye Institute, New York, New York 10032, USA. · Retina. · Pubmed #16205562 No free full text.

Abstract: PURPOSE: To assess the efficacy of intravitreal triamcinolone treatment for macular edema from central retinal vein occlusion (CRVO) and hemiretinal vein occlusion (HRVO). METHODS: This study was a retrospective medical records review of 24 eyes of 24 patients (mean age, 71 years) that were injected with 4 mg of intravitreal triamcinolone acetonide for treatment of macular edema due to CRVO (n = 21) and HRVO (n = 3). Of the 24 eyes, 14 were injected once, 6 were injected twice, 3 were injected 3 times, and 1 received 4 injections. Mean follow-up time was 10 months (range, 3-24 months). The average time between onset of symptoms and first injection was 5.4 months (range, 2-48 months). Available documents on pre- and postinjection optical coherence tomography central foveal thickness in 23 of 39 total injections were evaluated. RESULTS: All injections resulted in reduction in central foveal thickness as determined by optical coherence tomography. The mean central foveal thickness decreased to 55% of preinjection values ([n = 23] 635 vs. 352 mum, respectively; P < 0.001). The average gain in visual acuity was 1.3 Snellen lines (range, -3-7) over the course of the study period. Ten eyes gained > or =2 lines of visual acuity, 3 eyes improved 1 line, 7 eyes remained the same, and 4 eyes worsened. There was no correlation between improvement in foveal thickness and corresponding visual gain (P = 0.24). None of the eyes of diabetic patients (n = 6) or patients with ischemic CRVO (n = 2) improved in visual acuity. The difference in mean baseline (20/167) and mean final visual acuity (20/91) was statistically significant (P = 0.015). The mean best postinjection visual acuity (20/67) was also significantly higher than the mean final visual acuity (P = 0.019). When diabetic and ischemic CRVO patients were excluded, the difference between mean baseline visual acuity and mean final visual acuity was found to be highly significant ([n = 16] 20/133 vs. 20/67, respectively; P < 0.001), while mean final and best postinjection visual acuities (20/50) did not differ (P = 0.085). Eight of 16 phakic eyes showed progression of cataract, 2 of which underwent cataract extraction. Nine of 18 patients without a history of glaucoma developed ocular hypertension and required glaucoma medication during postinjection follow-up. Trabeculectomy was performed on two eyes with glaucoma. Two other eyes developed epiretinal membranes, one of which underwent vitrectomy. CONCLUSIONS: Intravitreal triamcinolone may be effective in treating macular edema from CRVO and HRVO. Subjects with concurrent diabetes or ischemic central retinal vein were less likely to have visual improvement.

Wang Z, Paik DC, Del Priore LV, Burch RL, Gaillard ER. · Department of Chemistry and Biochemistry, Northern Illinois University, DeKalb, Illinois 60115, USA. · Curr Eye Res. · Pubmed #16109650 No free full text.

Abstract: PURPOSE: Extracellular matrix (ECM) plays an important role in the regulation of cell function. The aging process may involve chemical modifications to ECM proteins, which may contribute to the aging of the Bruch membrane and pathogenesis of age-related macular degeneration (AMD). The purpose of this study is to investigate nitrite modification of basement membrane-like proteins on RPE cell behavior as a model for the aging of the Bruch membrane in age-related eye diseases. As a comparison, retinal pigment epithelium (RPE) cell behavior on glycolaldehyde-modified matrices (GMM) was also studied. METHODS: Growth factor reduced Matrigel was reacted with nitrite or glycolaldehyde for 1 week or 12 hr, respectively. Calf RPE cells were plated on the modified matrices and examined in several ways. Attachment rates, proliferation rates, apoptosis, and necrosis were determined. Cell morphology and cell susceptibility to A2E-mediated damage was also monitored. RESULTS: Nitrite-modified matrices (NMMs) inhibited cell attachment by 65% and proliferation by 33.7% compared to 69.6% and 21.7%, respectively, by GMM. Proliferation inhibition was not significant when cells were plated at high density on GMM (3.47%) but significant on NMM (20.9%). NMM induced cell apoptosis and necrosis, but GMM induced cell apoptosis only. Both modifications inhibited RPE differentiation. RPE cells on both matrices were more susceptible to blue light mediated damage by A2E, but damage was greater on NMM. CONCLUSIONS: NMM has significant damaging effects on RPE cell function and viability that is similar to the damaging effects of GMM. These studies may have relevance to the RPE dysfunction observed during the progression of AMD.

McLaughlin BJ, Fan W, Zheng JJ, Cai H, Del Priore LV, Bora NS, Kaplan HJ. · Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, Louisville, Kentucky, USA. · Invest Ophthalmol Vis Sci. · Pubmed #12882822 links to  free full text

Abstract: PURPOSE: There is increasing evidence that the complement system may play a significant role in one of the leading diseases causing blindness in the elderly population, age-related macular degeneration. In this study, a novel role in the retina for a regulatory protein in the complement system, CD46, is proposed. METHODS: The retinal pigment epithelium (RPE) was obtained from human donor eyes as well as human immortalized RPE cell lines (ARPE19). Immunohistochemistry and confocal microscopy were used to immunolocalize CD46 and beta1 integrin. Immunoprecipitation experiments with antibodies to either CD46 or beta1 integrin were performed on RPE cell lysates. A cell adhesion assay was used to determine the proportion of RPE cells that adhere to Bruch's membrane explants from donor eyes. RESULTS: Immunohistochemistry and confocal microscopy demonstrated that CD46 was polarized to the basal surface of the RPE along with beta1 integrin, shown previously to be involved in RPE adhesion. Immunoprecipitation experiments demonstrated that CD46 and beta1 integrin coprecipitated from RPE cell lysates when either protein was used as the precipitating antibody. The adhesion assay showed that antibodies to either CD46 or beta1 integrin reduced RPE adhesion to the surface of Bruch's membrane compared with the control. CONCLUSIONS: These findings suggest that this complement regulatory protein, which protects host cells from autologous complement attack, may have a functional interaction with beta1 integrin in the eye that is related to RPE adhesion to its basement membrane and Bruch's membrane.

Del Priore LV, Kaplan HJ, Tezel TH, Hayashi N, Berger AS, Green WR. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. · Am J Ophthalmol. · Pubmed #11292411 No free full text.

Abstract: PURPOSE: To report the histopathology after retinal pigment epithelial cell transplantation and subfoveal membranectomy in age-related macular degeneration. METHODS: An 85-year-old white woman with bilateral choroidal neovascularization underwent subfoveal membranectomy combined with transplantation of a sheet of human adult retinal pigment epithelium (retinal pigment epithelium) under the foveal center in the right eye. The patient was immunosuppressed postoperatively with prednisone, cyclosporine, and azathioprine. The patient died from congestive heart failure 114 days after surgery. RESULTS: A patch of hyperpigmentation was visible at the transplant site under the foveola after surgery. Mound-like clusters of individual round, large densely pigmented cells were present in the subretinal space and outer retina in this area. There was loss of the photoreceptor outer segments and native retinal pigment epithelium in the center of the transplant bed, with disruption of the outer nuclear layer predominantly over regions of multilayered pigmented cells. Cystic spaces were present in the inner and outer retina. A residual intra-Bruchs membrane component of the original choroidal neovascular complex was present under the transplant site. CONCLUSIONS: The transplant site contained clusters of round, pigmented cells that did not form a uniform monolayer in most areas. The morphology at the transplant site is consistent with the lack of visual improvement seen after surgery in this patient.

Tezel TH, Del Priore LV. · Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, Missouri, USA. · Invest Ophthalmol Vis Sci. · Pubmed #10067982 links to  free full text

Abstract: PURPOSE: To determine the morphology of human retinal pigment epithelium (RPE) after reattachment to different ultrastructural layers of human Bruch's membrane (BM). METHODS: Bruch's membrane explants were prepared from eyes of 23 human donors (age range, 11-89 years). The basal lamina of the RPE, inner collagenous layer, and elastin layer were removed sequentially by mechanical and enzymatic techniques. First-passage cells of human RPE (15,000 cells/6 mm explant) from three donors (ages, 52, 64, and 80 years) were plated onto different layers of human BM, and the explants were examined by scanning and transmission electron microscopy up to 21 days later. RESULTS: RPE flattened and extended footplates 6 hours after plating onto basal lamina. Cells remained round 6 and 24 hours after plating onto the inner collagenous, elastin, or outer collagenous layer. The RPE cells became confluent 14 days after plating onto basal lamina but did not become confluent up to 21 days after plating onto the inner collagenous or elastin layer. Sparse round cells were observed 21 days after plating onto deeper layers, suggesting extensive loss of RPE. CONCLUSIONS: The morphology and subsequent behavior of the RPE reattached to BM depends on the anatomic layer of BM available for cell reattachment. The results suggest that the ability of transplanted RPE to repopulate BM in age-related macular degeneration and other disorders may depend on the layer of BM available to serve as a substrate for cell reattachment.

Greene AB, Del Priore LV, Iranmanesh R. · No affiliation provided · Br J Ophthalmol. · Pubmed #16929073 No free full text.

This publication has no abstract.