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[PMID]: 26845053
[Au] Autor:Aminsharifi A; Hekmati P; Noorafshan A; Karbalay-Doost S; Nadimi E; Aryafar A; Hosseinabadi OK; Naseri MM; ZarePoor M
[Ad] Address:Department of Urology, Shiraz University of Medical Sciences, Shiraz, Iran; Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. Electronic address: aminsharifi_ar@yahoo.com....
[Ti] Title:Scrotal Cooling to Protect Against Cisplatin-induced Spermatogenesis Toxicity: Preliminary Outcome of an Experimental Controlled Trial.
[So] Source:Urology;91:90-8, 2016 May.
[Is] ISSN:1527-9995
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:OBJECTIVE: To investigate the protective effects of scrotal cooling on cisplatin-induced gonadal toxicity in an animal model. METHODS: Twenty-one male BALB/c mice were divided into 3 groups. The cisplatin group received 2 cycles of cisplatin (2.5 mg/kg/day for 5 days with 16 days of recovery) intraperitoneally, and the cisplatin + cooling group received the same regimen of cisplatin with a cooling protocol: cooling induction for 30 minutes before injection and cooling for 60 minutes after injection. Mice in control group were given an injection of 2 mL normal saline intraperitoneally. After 35 days of recovery (1 cycle of spermatogenesis), the volume of the testes (Cavalieri method), volume density of the tubules and epithelium (point-counting method), and number of cells (optical dissector method) were estimated. RESULTS: The volume of the testes, tubules, and epithelium was reduced between 61% and 66%, and the number of the spermatogonia, spermatocytes, round spermatids, and long spermatids was reduced between 70% and 93% in cisplatin group compared with that of control mice. Cisplatin affected spermatids to a greater extent, and Sertoli cells to a lesser extent than the other cells. The volume and number of the cells were reduced in the cisplatin + cooling group but to a lesser extent compared with those of mice in the cisplatin group. Sertoli cells were more intact in the cisplatin + cooling group compared with those of the control group. CONCLUSION: Scrotal cooling during cisplatin administration seems to have beneficial effects on spermatogenesis. Scrotal cooling may hold promise as a way to protect fertility.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

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[PMID]: 27107362
[Au] Autor:Rebolleda G; García-Montesinos J; Muñoz-Negrete FJ; González-López JJ
[Ad] Address:Department of Ophthalmology, Hospital Universitario Ramón y Cajal, Madrid, Spain....
[Ti] Title:Re: Wang et al.: Acute peripapillary retinal pigment epithelium changes associated with acute intraocular pressure elevation (Ophthalmology 2015,122:2022-8).
[So] Source:Ophthalmology;123(5):e34-5, 2016 May.
[Is] ISSN:1549-4713
[Cp] Country of publication:United States
[La] Language:eng
[Pt] Publication type:LETTER
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  3 / 264796 MEDLINE  
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[PMID]: 26896125
[Au] Autor:Basu S; Sureka SP; Shanbhag SS; Kethiri AR; Singh V; Sangwan VS
[Ad] Address:Tej Kohli Cornea Institute, L. V. Prasad Eye Institute, Hyderabad, India; Center for Regenerative Ophthalmology, L. V. Prasad Eye Institute, Hyderabad, India; Prof. Brien Holden Eye Research Center, Champalimaud Translational Centre for Eye Research, L. V. Prasad Eye Institute, Hyderabad, India....
[Ti] Title:Simple Limbal Epithelial Transplantation: Long-Term Clinical Outcomes in 125 Cases of Unilateral Chronic Ocular Surface Burns.
[So] Source:Ophthalmology;123(5):1000-10, 2016 May.
[Is] ISSN:1549-4713
[Cp] Country of publication:United States
[La] Language:eng
[Ab] Abstract:PURPOSE: This study describes the long-term clinical outcomes of autologous simple limbal epithelial transplantation (SLET), a relatively new technique of limbal stem cell transplantation. DESIGN: This was a single-center prospective interventional cases series. PARTICIPANTS: This study included 125 patients, 65 adults and 60 children who developed unilateral limbal stem cell deficiency (LSCD) after suffering with ocular surface burns and underwent SLET between 2010 and 2014. METHODS: A 1-clock hour limbal biopsy sample was obtained from the unaffected eye. At the same sitting, the recipient eye was surgically prepared and the donor tissue was divided into small pieces and transplanted using an amniotic membrane scaffold with fibrin glue. MAIN OUTCOME MEASURES: The diagnosis and outcome in every case was validated by 5 independent masked assessors. The primary outcome measure was restoration of a completely epithelized, stable, and avascular corneal surface. The secondary outcome measure was improvement in visual acuity. Complications, risk factors for failure, and immunohistochemistry analysis of corneas that underwent SLET also were described. RESULTS: At a median postoperative follow-up of 1.5 years (range, 1-4 years), 95 of 125 eyes (76%; 95% confidence interval, 68.5%-83.5%) maintained a successful outcome. Kaplan-Meier analysis revealed a comparable survival probability at 1 year of 80% in adults and 72% in children (P = 0.304). Two-line improvement in visual acuity was seen in 75.2%, and 67% of successful cases attained 20/60 or better vision (P < 0.0001). Progressive conjunctivalization occurred in 18.4% of eyes. The clinical factors associated with failure were identified as acid injury, severe symblepharon, SLET combined with keratoplasty, and postoperative loss of transplants (P ≤ 0.0075). Success rates were comparable among faculty and trainees (P = 0.71). Immunohistochemistry revealed successful regeneration of normal corneal epithelium (CK3(+)/12(+)) without admixture of conjunctiva cells (Muc5AC(-)/CK19(-)) and replenishment of limbal stem cell (ΔNp63α(+)/ABCG2(+)) reserve. CONCLUSIONS: Autologous SLET is an effective, reliable and replicable technique for long-lasting corneal regeneration and vision restoration in unilateral chronic ocular surface burns. Simple limbal epithelial transplantation is probably preferable to other techniques of limbal stem cell transplantation, particularly where cell cultivation facilities are unavailable.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  4 / 264796 MEDLINE  
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[PMID]: 26948455
[Au] Autor:Takir S; Gürel-Gürevin E; Toprak A; Demirci-Tansel C; Uydes-Dogan BS
[Ad] Address:Department of Pharmacology, Faculty of Pharmacy, Istanbul University, Istanbul, Turkey; Department of Medical Pharmacology, Section of Internal Medical Sciences, Faculty of Medicine, Giresun University, Giresun, Turkey. Electronic address: selcuk_takir@yahoo.com....
[Ti] Title:The elevation of intraocular pressure is associated with apoptosis and increased immunoreactivity for nitric oxide synthase in rat retina whereas the effectiveness of retina derived relaxing factor is unaffected.
[So] Source:Exp Eye Res;145:401-11, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Glaucoma is a progressive ocular disease that stands in the upper rank for the cause of blindness in worldwide. In the present study, we aimed to elucidate the possible disturbances occurred in the layers of retina due to an increase in intraocular pressure (IOP) and to verify the effectiveness of retina derived relaxing factor, i.e., RRF in this pathologic condition. The increase in IOP was induced by cauterization of the three of episcleral veins simultaneously in rats. After 8 weeks period, the retinas excised from the vein cauterized eyes were evaluated for the possible histopathological and ultrastructural alterations as well as for the relaxing effects on isolated bovine retinal and rat mesenteric arteries, in comparison with the retinas obtained from contralateral sham-operated eyes. In the retinas of IOP-elevated eyes, profound morphological deteriorations were determined in the ganglion and outer nuclear cell layers which were associated with an increased number of TUNEL positive cells in the ganglion and inner nuclear cell layers. Increased immunohistochemical stainings for three isoforms of nitric oxide synthase (NOS) were defined in almost all layers of the retinas of IOP-elevated eyes, in which eNOS was abundant particularly in the inner plexiform and ganglion cell layers. An irregular basal folding of retinal pigment epithelium (RPE) and an increased inter lamellar space of photoreceptor cell layer furtherly characterized the prominent degeneration of those layers in the retinas of IOP-elevated eyes. On the other hand, the relaxing effects of the retina obtained from IOP-elevated eyes were determined to be unchanged on the retinal and mesenteric arteries precontracted either with prostaglandin F2α (PGF2α, 30 µM) or potassium chloride (K(+), 100 mM), when compared with the relaxations of control retina obtained from contralateral sham-operated eyes. Overall, these findings suggested that the elevation of IOP induces prominent structural changes in rat retina particularly in the ganglion and inner layers that is associated with marked apoptosis and increased immunoreactivity for NOS, while the functional effectiveness of retina derived relaxing factor, i.e., RRF is unaffected.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  5 / 264796 MEDLINE  
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[PMID]: 26923800
[Au] Autor:Leaderer D; Cashman SM; Kumar-Singh R
[Ad] Address:Department of Ophthalmology, Program in Genetics, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111, USA.
[Ti] Title:G-quartet oligonucleotide mediated delivery of proteins into photoreceptors and retinal pigment epithelium via intravitreal injection.
[So] Source:Exp Eye Res;145:380-92, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:There is currently no available method to efficiently deliver proteins across the plasma membrane of photoreceptor or retinal pigment epithelium (RPE) cells in vivo. Thus, current clinical application of recombinant proteins in ophthalmology is limited to the use of proteins that perform their biological function extracellularly. The ability to traverse biological membranes would enable the mobilization of a significantly larger number of proteins with previously well characterized properties. Nucleolin is abundantly present on the surface of rapidly dividing cells including cancer cells. Surprisingly, nucleolin is also present on the surface of photoreceptor cell bodies. Here we investigated whether nucleolin can be utilized as a gateway for the delivery of proteins into retinal cells following intravitreal injection. AS1411 is a G-quartet aptamer capable of targeting nucleolin. Subsequent to intravitreal injection, fluorescently labeled AS1411 localized to various retinal cell types including the photoreceptors and RPE. AS1411 linked to streptavidin (a ∼50 kDa protein) via a biotin bridge enabled the uptake of Streptavidin into photoreceptors and RPE. AS1411-Streptavidin conjugate applied topically to the cornea allowed for uptake of the conjugate into the nucleus and cytoplasm of corneal endothelial cells. Clinical relevance of AS1411 as a delivery vehicle was strongly indicated by demonstration of the presence of cell surface nucleolin on the photoreceptors, inner neurons and ganglion cells of human retina. These data support exploration of AS1411 as a means of delivering therapeutic proteins to diseased retina.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  6 / 264796 MEDLINE  
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[PMID]: 26880020
[Au] Autor:Kubilus JK; Beazley KE; Talbot CJ; Linsenmayer TF
[Ad] Address:Integrative Physiology and Pathobiology Department, Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA, United States. Electronic address: james.kubilus@tufts.edu....
[Ti] Title:Nuclear ferritin mediated regulation of JNK signaling in corneal epithelial cells.
[So] Source:Exp Eye Res;145:337-40, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Corneal epithelial (CE) cells are exposed to environmental insults (e.g., UV-irradiation), yet they suffer little damage. Our previous studies suggest that chicken CE cells have a novel form of protection involving having ferritin in a nuclear location where it can bind to DNA and sequester free iron. Here we describe another potential nuclear ferritin-mediated protective mechanism: the down-regulation of the JNK signaling pathway. The JNK pathway has been shown by others to promote apoptosis in response to cell damage and also to be activated in CE cell lines following exposure to UV radiation. Here we show in COS7 reporter cell lines that the expression of ferritin in a nuclear localization significantly down-regulates the JNK pathway (p = 5.7 × 10(-6)), but has no effect on the NFkB or the Erk pathways. In organ cultures of embryonic chicken corneas, we observed that inhibiting the synthesis of nuclear ferritin in CE cells, using the iron-chelating molecule deferoxamine, led to an increase in JNK signaling, as measured by phospho-JNK levels compared to CE cells with nuclear ferritin. Furthermore, the chemical inhibition of the JNK pathway using the molecule AS601245 decreased the production of nuclear ferritin. Taken together, these observations suggest that in CE cells a feedback-loop exists in which JNK signaling increases the production of nuclear ferritin and, in turn, nuclear ferritin decreases the activity of the JNK signaling pathway.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  7 / 264796 MEDLINE  
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[PMID]: 26854824
[Au] Autor:Pfeffer BA; Xu L; Porter NA; Rao SR; Fliesler SJ
[Ad] Address:Research Service, VA Western New York Healthcare System, Buffalo, NY, USA; SUNY Eye Institute, Buffalo, NY, USA; Departments of Ophthalmology and Biochemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY, USA....
[Ti] Title:Differential cytotoxic effects of 7-dehydrocholesterol-derived oxysterols on cultured retina-derived cells: Dependence on sterol structure, cell type, and density.
[So] Source:Exp Eye Res;145:297-316, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Tissue accumulation of 7-dehydrocholesterol (7DHC) is a hallmark of Smith-Lemli-Opitz Syndrome (SLOS), a human inborn error of the cholesterol (CHOL) synthesis pathway. Retinal 7DHC-derived oxysterol formation occurs in the AY9944-induced rat model of SLOS, which exhibits a retinal degeneration characterized by selective loss of photoreceptors and associated functional deficits, Müller cell hypertrophy, and engorgement of the retinal pigment epithelium (RPE) with phagocytic inclusions. We evaluated the relative effects of four 7DHC-derived oxysterols on three retina-derived cell types in culture, with respect to changes in cellular morphology and viability. 661W (photoreceptor-derived) cells, rMC-1 (Müller glia-derived) cells, and normal diploid monkey RPE (mRPE) cells were incubated for 24 h with dose ranges of either 7-ketocholesterol (7kCHOL), 5,9-endoperoxy-cholest-7-en-3ß,6α-diol (EPCD), 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), or 4ß-hydroxy-7-dehydrocholesterol (4HDHC); CHOL served as a negative control (same dose range), along with appropriate vehicle controls, while staurosporine (Stsp) was used as a positive cytotoxic control. For 661W cells, the rank order of oxysterol potency was: EPCD > 7kCHOL >> DHCEO > 4HDHC ≈ CHOL. EC50 values were higher for confluent vs. subconfluent cultures. 661W cells exhibited much higher sensitivity to EPCD and 7kCHOL than either rMC-1 or mRPE cells, with the latter being the most robust when challenged, either at confluence or in sub-confluent cultures. When tested on rMC-1 and mRPE cells, EPCD was again an order of magnitude more potent than 7kCHOL in compromising cellular viability. Hence, 7DHC-derived oxysterols elicit differential cytotoxicity that is dose-, cell type-, and cell density-dependent. These results are consistent with the observed progressive, photoreceptor-specific retinal degeneration in the rat SLOS model, and support the hypothesis that 7DHC-derived oxysterols are causally linked to that retinal degeneration as well as to SLOS.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
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[St] Status:In-Data-Review

  8 / 264796 MEDLINE  
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[PMID]: 26854823
[Au] Autor:Ferrington DA; Kapphahn RJ; Leary MM; Atilano SR; Terluk MR; Karunadharma P; Chen GK; Ratnapriya R; Swaroop A; Montezuma SR; Kenney MC
[Ad] Address:Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: ferri013@umn.edu....
[Ti] Title:Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration.
[So] Source:Exp Eye Res;145:269-77, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:Age-related macular degeneration (AMD) is a major cause of blindness among the elderly in the developed world. Genetic analysis of AMD has identified 34 high-risk loci associated with AMD. The genes at these high risk loci belong to diverse biological pathways, suggesting different mechanisms leading to AMD pathogenesis. Thus, therapies targeting a single pathway for all AMD patients will likely not be universally effective. Recent evidence suggests defects in mitochondria (mt) of the retinal pigment epithelium (RPE) may constitute a key pathogenic event in some AMD patients. The purpose of this study is to determine if individuals with a specific genetic background have a greater propensity for mtDNA damage. We used human eyebank tissues from 76 donors with AMD and 42 age-matched controls to determine the extent of mtDNA damage in the RPE that was harvested from the macula using a long extension polymerase chain reaction assay. Genotype analyses were performed for ten common AMD-associated nuclear risk alleles (ARMS2, TNFRSF10A, CFH, C2, C3, APOE, CETP, LIPC, VEGF and COL10A1) and mtDNA haplogroups. Sufficient samples were available for genotype association with mtDNA damage for TNFRSF10A, CFH, CETP, VEGFA, and COL10A1. Our results show that AMD donors carrying the high risk allele for CFH (C) had significantly more mtDNA damage compared with donors having the wild-type genetic profile. The data from an additional 39 donors (12 controls and 27 AMD) genotyped for CFH alleles further supported these findings. Taken together, these studies provide the rationale for a more personalized approach for treating AMD by uncovering a significant correlation between the CFH high risk allele and accelerated mtDNA damage. Patients harboring this genetic risk factor may benefit from therapies that stabilize and protect the mt in the RPE.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  9 / 264796 MEDLINE  
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[PMID]: 26778749
[Au] Autor:Hamilton PW; Sun Y; Henry JJ
[Ad] Address:Department of Cell & Developmental Biology, University of Illinois, 601 S. Goodwin Ave. Urbana, IL 61801, USA.
[Ti] Title:Lens regeneration from the cornea requires suppression of Wnt/ß-catenin signaling.
[So] Source:Exp Eye Res;145:206-15, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:The frog, Xenopus laevis, possesses a high capacity to regenerate various larval tissues, including the lens, which is capable of complete regeneration from the cornea epithelium. However, the molecular signaling mechanisms of cornea-lens regeneration are not fully understood. Previous work has implicated the involvement of the Wnt signaling pathway, but molecular studies have been very limited. Iris-derived lens regeneration in the newt (Wolffian lens regeneration) has shown a necessity for active Wnt signaling in order to regenerate a new lens. Here we provide evidence that the Wnt signaling pathway plays a different role in the context of cornea-lens regeneration in Xenopus. We examined the expression of frizzled receptors and wnt ligands in the frog cornea epithelium. Numerous frizzled receptors (fzd1, fzd2, fzd3, fzd4, fzd6, fzd7, fzd8, and fzd10) and wnt ligands (wnt2b.a, wnt3a, wnt4, wnt5a, wnt5b, wnt6, wnt7b, wnt10a, wnt11, and wnt11b) are expressed in the cornea epithelium, demonstrating that this tissue is transcribing many of the ligands and receptors of the Wnt signaling pathway. When compared to flank epithelium, which is lens regeneration incompetent, only wnt11 and wnt11b are different (present only in the cornea epithelium), identifying them as potential regulators of cornea-lens regeneration. To detect changes in canonical Wnt/ß-catenin signaling occurring within the cornea epithelium, axin2 expression was measured over the course of regeneration. axin2 is a well-established reporter of active Wnt/ß-catenin signaling, and its expression shows a significant decrease at 24 h post-lentectomy. This decrease recovers to normal endogenous levels by 48 h. To test whether this signaling decrease was necessary for lens regeneration to occur, regenerating eyes were treated with either 6-bromoindirubin-3'-oxime (BIO) or 1-azakenpaullone - both activators of Wnt signaling - resulting in a significant reduction in the percentage of cases with successful regeneration. In contrast, inhibition of Wnt signaling using either the small molecule IWR-1, treatment with recombinant human Dickkopf-1 (rhDKK1) protein, or transgenic expression of Xenopus DKK1, did not significantly affect the percentage of successful regeneration. Together, these results suggest a model where Wnt/ß-catenin signaling is active in the cornea epithelium and needs to be suppressed during early lens regeneration in order for these cornea cells to give rise to a new lentoid. While this finding differs from what has been described in the newt, it closely resembles the role of Wnt signaling during the initial formation of the lens placode from the surface ectoderm during early embryogenesis.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review

  10 / 264796 MEDLINE  
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[PMID]: 26775053
[Au] Autor:Lambert NG; Zhang X; Rai RR; Uehara H; Choi S; Carroll LS; Das SK; Cahoon JM; Kirk BH; Bentley BM; Ambati BK
[Ad] Address:Ambati Lab, John A. Moran Eye Center, Salt Lake City, UT, USA....
[Ti] Title:Subretinal AAV2.COMP-Ang1 suppresses choroidal neovascularization and vascular endothelial growth factor in a murine model of age-related macular degeneration.
[So] Source:Exp Eye Res;145:248-57, 2016 Apr.
[Is] ISSN:1096-0007
[Cp] Country of publication:England
[La] Language:eng
[Ab] Abstract:To assess whether Tie2-mediated vascular stabilization ameliorates neovascular age-related macular degeneration (AMD), we investigated the impact of adeno-associated virus-mediated gene therapy with cartilage oligomeric matrix protein angiopoietin-1 (AAV2.COMP-Ang1) on choroidal neovascularization (CNV), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF) in a mouse model of the disease. We treated mice with subretinal injections of AAV2.COMP-Ang1 or control (AAV2.AcGFP, AAV2.LacZ, and phosphate-buffered saline). Subretinal AAV2 localization and plasmid protein expression was verified in the retinal pigment epithelium (RPE)/choroid of mice treated with all AAV2 constructs. Laser-assisted simulation of neovascular AMD was performed and followed by quantification of HIF, VEGF, and CNV in each experimental group. We found that AAV2.COMP-Ang1 was associated with a significant reduction in VEGF levels (29-33%, p < 0.01) and CNV volume (60-70%, p < 0.01), without a concomitant decrease in HIF1-α, compared to all controls. We concluded that a) AAV2 is a viable vector for delivering COMP-Ang1 to subretinal tissues, b) subretinal COMP-Ang1 holds promise as a prospective treatment for neovascular AMD, and c) although VEGF suppression in the RPE/choroid may be one mechanism by which AAV2.COMP-Ang1 reduces CNV, this therapeutic effect may be hypoxia-independent. Taken together, these findings suggest that AAV2.COMP-Ang1 has potential to serve as an alternative or complementary option to anti-VEGF agents for the long-term amelioration of neovascular AMD.
[Pt] Publication type:JOURNAL ARTICLE
[Em] Entry month:1604
[Js] Journal subset:IM
[St] Status:In-Data-Review


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