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BACKGROUND AND OBJECTIVE: To evaluate the safety and efficacy of 1.0 mg risuteganib in subjects with nonexudative age-related macular degeneration (AMD). PATIENTS AND METHODS: This was a phase 2a, prospective, double-masked, sham-controlled study. Eyes with nonexudative (dry) AMD and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA) between 20/40 and 20/200 were included. Subjects were randomized to intravitreal 1.0 mg risuteganib or sham injection. At Week 16, subjects in the risuteganib group received a second 1.0-mg dose and the sham group crossed over to receive a dose of 1.0 mg risuteganib and were evaluated at Week 28. The primary endpoint was proportion of subjects with 8 letters ETDRS or more BCVA gain from baseline to Week 28 in the risuteganib group versus baseline to Week 12 for the sham group. BCVA was tested and subjects were observed for adverse events (AEs) every 4 weeks until completion of the study at 32 weeks. RESULTS: Forty-five subjects (risuteganib, n = 29; sham, n = 16) were enrolled in the study, of whom 39 (risuteganib, n = 25; sham, n = 14) completed the study and were included in the per protocol efficacy analysis. At baseline, mean age was 78.8 and 75.9 years and mean BCVA was 67.1 and 64.4 letters in the sham and risuteganib groups, respectively. The primary endpoint was met by 48% of the risuteganib group at Week 28 and 7% of the sham group at Week 12 ( P = .013). Of the risuteganib subjects, 20% gained 15 letters or more at Week 28, whereas no patients in the sham group at Week 12 achieved this visual acuity gain. The only ocular treatment-related treatment-emergent AE was vitreous floaters, which spontaneously recovered without sequelae. No drug-related serious AE was reported. CONCLUSIONS: Risuteganib demonstrated significant BCVA improvement in patients with non-exudative AMD. No drug-related AEs were seen during a 32-week observation period. [ Ophthalmic Surg Lasers Imaging Retina . 2021;52:327–335.]

Since mitochondrial dysfunction is implicated in the pathogenesis of AMD, this study is based on the premise that repurposing of mitochondria-stabilizing FDA-approved drugs such as PU-91, might rescue AMD RPE cells from AMD mitochondria-induced damage. The PU-91 drug upregulates PGC-1α which is a critical regulator of mitochondrial biogenesis. Herein, we tested the therapeutic potential of PU-91 drug and examined the additive effects of treatment with PU-91 and esterase inhibitors i.e., EI-12 and EI-78, using the in vitro transmitochondrial AMD cell model. This model was created by fusing platelets obtained from AMD patients with Rho0 i.e., mitochondria-deficient, ARPE-19 cell lines. The resulting AMD RPE cell lines have identical nuclei but differ in their mitochondrial DNA content, which is derived from individual AMD patients. Briefly, we report significant improvement in cell survival, mitochondrial health, and antioxidant potential in PU-91-treated AMD RPE cells compared to their untreated counterparts. In conclusion, this study identifies PU 91 as a therapeutic candidate drug for AMD and repurposing of PU-91 will be a smoother transition from lab bench to clinic since the pharmacological profiles of PU-91 have been examined already.

Background Despite the good outcomes achieved with intravitreal angiogenic therapy, a subset of neovascular age-related macular degeneration (AMD) patients experience resistance to therapy after repeated injections. Switching drugs could offer benefit to this group of patients. Purpose To determine visual and anatomical outcomes in a cohort of neovascular AMD patients resistant to repeated injections of bevacizumab/ranibizumab after switching to aflibercept therapy. Methods This was a retrospective chart review of patients who had a diagnosis of neovascular AMD and persistent intraretinal (IRF) and/or subretinal fluid (SRF) on optical coherence tomography (OCT) for at least 3 months despite monthly bevacizumab and/or ranibizumab injections prior to transition to aflibercept. We reviewed patients’ records and OCT images obtained at baseline, 1, 3, 6 and 12 months after transition to aflibercept. Data collected included demographics, best-corrected visual acuity (BCVA), number of injections received and the occurrence of any adverse events. Studied OCT parameters included central macular thickness (CMT) values and the presence or absence of SRF, IRF and/or pigment epithelial detachment (PED) at each visit. Results We included 53 eyes of 48 patients. Mean change in BCVA from baseline was 0.05 ± 0.13 (P = 0.01) at M1, 0.04 ± 0.16 (P = 0.08) at M3, 0.01 ± 0.22 (P = 0.9) at M6, and 0.02 ± 0.28 (P = 1) at M12, while the mean change in CMT from baseline was 64 ± 75 μm (P Conclusion Switching to intravitreal aflibercept therapy in a cohort of neovascular AMD patients resistant to chronic bevacizumab and/or ranibizumab injections can lead to significant visual improvement in the short term and sustained reduction of central macular thickness over 1 year of followup.

BACKGROUND AND OBJECTIVE: Visual outcomes of the FAME study (0.2 μg/day fluocinolone acetonide [FAc]) and Protocol I (0.5 mg ranibizumab plus deferred laser) were compared using the area under the curve (AUC) analysis method. PATIENTS AND METHODS: Best-corrected visual acuity (BCVA) data collected during a period of 3 years of follow-up for patients enrolled in FAME or Protocol I were used to calculate AUC of the change in BCVA over a time curve. RESULTS: In the overall population, there was a greater treatment effect for ranibizumab plus deferred laser compared with FAc. However, for subgroups of pseudophakic eyes, eyes with chronic diabetic macular edema (DME), and pseudophakic eyes with chronic DME, ranibizumab plus deferred laser and FAc were not found to be significantly different. The ranibizumab group received a median of 14 injections during a 36-month period compared with a mean of 1.3 injections in the FAc group. CONCLUSION: In pseudophakic and chronic DME subgroups, FAc was comparable to ranibizumab plus deferred laser with fewer injections. [ Ophthalmic Surg Lasers Imaging Retina . 2018;49:698–706.]

The antivascular endothelial growth factor agents have brought a paradigm shift in the treatment strategy of neovascular age-related macular degeneration (nAMD) by making the approach more interventional. Optical coherence tomography (OCT) is the critical clinical tool used for assessing the lesion activity and the need for therapy, and the presence of fluid is the key biomarker. We have noticed that there has been a lot of discussion and analysis to understand the fluid seen on spectral-domain OCT (SD-OCT) in the recent past. Most of the data and interpretation are based on the post hoc analysis of the Comparison of Age-Related Macular Degeneration Treatment Trials and VIEW 2 trials.1 2 Understanding the tolerance towards subretinal fluid (SRF) was demonstrated by the FLUID trial.3 The recent post hoc analysis of HARBOR trial measured the artificial intelligence-based fluid volume (IRF and SRF) and its prognostic value.4 Common interpretation and perception on the basis of evidences described above say that intraretinal fluid (IRF) either at baseline or at any stage of the treatment is a sign of poor visual prognosis in the long term. On the contrary, some amount of SRF can be tolerated. Subretinal pigment epithelial (sub-RPE) fluid can also be carefully monitored if associated with good visual acuity. However, this may not be completely true for the entire spectrum of nAMD. Jung et al 5 reported the incidence of the three subtypes of neovascularisation in AMD with the use of SD-OCT. They found that type 3 macular neovascularisation (MNV) comprised 28%–34% of eyes with neovascular AMD which is much higher than what was …

The last decade has seen a paradigm shift in the management of neovascular age-related macular degeneration (nAMD) with the introduction of biologicals that inhibit vascular endothelial growth factor (VEGF). These agents, similar to biologicals have imposed a major burden on all healthcare systems. Patients are not only financially strained by the cost of intravitreal injections that require repeated administrations but multiple visits to the hospital compromise quality of life. The recognition of this burden has to some extent led to a shift in the dosing strategy from fixed monthly (of ranibizumab) or 8-weekly dosing (of aflibercept) to pro-re-nata and treat-and-extend (T&E) protocols.1 After the three initial loading doses, re-injection decisions are made based on the presence of fluid on optical coherence tomography (OCT). The OCT is a tool that demonstrates structural changes in the macular retina arising from leakage in the nAMD lesion or occurring as part of the sequelae of chronicity of the pathology. Leakage of fluid and blood constituents representing lesion activity is interpreted by detecting signs (biomarkers) seen on OCT. The presence of clear hypo-reflective regions within the intraretinal layers is considered to represent fluid accumulation. Depending on the location of these regions of hypo-reflectivity, they can be compartmentalised into intraretinal fluid (IRF), subretinal fluid (SRF) and subretinal pigment epithelial fluid. Multiple post hoc analyses of major trials such as the Comparison of AMD Treatments Trials (CATT) and VIEW 2 have shown that presence of IRF, either foveal or extra-foveal during the …

Purpose: To analyse the intraocular pressure rise after intravitreal dexamethasone implant (Ozurdex) amongst different geographic populations. Methods: The medical charts of 294 dexamethasone implants between February 2011 and 2017 were reviewed retrospectively. South Asian (India), White (Europe, US and Israel) Latino (Argentina and Brazil) patient data was included in the study. Ocular hypertension (OHT) was defined as intraocular pressure of >25 mmHg or an increase of at least 10 mmHg from baseline. The main indications for treatment were diabetic macular edema (ME) (65.6%), retinal vein occlusion (26.5%), uveitis (7.8%). Results: Amongst 294 intravitreal implants, ocular hypertension (>25 mmHg) was recorded in 0, 8 and 9.5% in White, Latino, and South Asian groups, respectively. However, IOP > 20 mmHg was recorded in 14%, 28% and 27% in White, Latino, and South Asian groups, respectively. Incidence of very high IOP (>35 mmHg) was lower in all geographical groups. It was 3% in Latino followed by 2% in South Asian group. Conclusion: Latino and South Asian groups have higher IOP rise compared to White population. Most patients with elevated IOP fluctuate between 20–25 mmHg.

Purpose: To investigate if use of adjunctive intravitreal dexamethasone implant during pars plana vitrectomy (PPV) leads to faster visual recovery and reduction of retinal thickness in idiopathic epiretinal membrane (ERM). Methods: In this non-randomized, comparative, interventional study 30 eyes (from 30 patients with idiopathic ERM) were enrolled. In the control group (n = 15), patients underwent 25-G pars plana vitrectomy (PPV) and ERM peeling. In the study group (n = 15), each patient underwent the same procedure as those in the control group, and also received an additional dexamethasone implant. Primary outcome after treatment was mean gain in best corrected visual acuity (BCVA), and secondary outcome was reduction in central retinal thickness (CRT). Data were analyzed using Fisher's exact test, Wilcoxon rank sum test, and two-sample t-test. Results: The mean gain in BCVA (logMAR) from baseline at 1-month follow-up was significantly higher in the study group (median = -0.3, IQR = -0.4, -0.1) than in the control group (median = 0, IQR = -0.1, 0.3; P < 0.008). However, no significant difference in mean gain in BCVA between the two groups was detectable at the 6-month follow-up (P < 0.55). At 1-month follow-up, one and seven patients in the control and study groups gained ≥15 letters of BCVA (P < 0.05), respectively. The mean reductions in CRT at the 1-month follow-up were significantly higher in the study group than in the control group (Mean = -60 μm, SD = 92.1; P < 0.014; 95% CI = 19.75–156.54). The difference in mean reduction of CRT at 6 months was not significant (P < 0.24). Conclusion: Adjunctive dexamethasone implant can aid faster visual recovery after PPV in idiopathic ERM, although the implants do not affect long-term gains in visual acuity.

Background Prader–Willi syndrome (PWS) is a genetic disease caused by loss of expression of the paternally inherited copy of several genes on the long arm of chromosome 15. Ophthalmic manifestations of PWS include strabismus, amblyopia, nystagmus, hypopigmentation of the iris and choroid, diabetic retinopathy, cataract and congenital ectropion uvea. An overlap between PWS and oculocutaneous albinism (OCA) has long been recognized and attributed to deletion of OCA2 gene located in PWS critical region (PWCR). Case report A 30-year-old male patient with PWS presented with vision loss in his left eye. His right eye had normal visual acuity. Multimodal imaging revealed absence of a foveal depression and extremely reduced diameter of the foveal avascular zone in the right eye and an inactive type 2 macular neovascular lesion in the left eye. Conclusions We report a presumed association of fovea plana and choroidal neovascularization with PWS. The use of multimodal imaging revealed novel findings in a PWS patient that might enrich our current understanding of the overlap between PWS and OCA.

To report the safety of intravitreal ocriplasmin injection based on 2 Phase 3 clinical trials in patients with symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with full-thickness macular holes.Safety analyses were based on 2 completed Phase 3 studies assessing intravitreal ocriplasmin injection. Adverse events (AEs), serious AEs, and suspected adverse drug reactions are reported. The authors also report AEs of special interest from 8 other completed Phase 2 studies and 2 ongoing studies.A total of 465 eyes were injected with ocriplasmin (125 µg), and 187 eyes were treated with placebo injection in Phase 3 studies. Overall AE rate was 69.0% in the placebo group and 76.6% for ocriplasmin-treated patients. Most AEs were in the study eye, mild or moderate in severity, and transient. All suspected adverse drug reactions were ocular; the majority was nonserious, of mild intensity, and transient.Intravitreal ocriplasmin injection provides a generally well-tolerated pharmacologic treatment option for patients with symptomatic vitreomacular adhesion/vitreomacular traction, including when associated with full-thickness macular holes ≤400 µm in diameter.

Purpose: To evaluate the efficacy and safety of dexamethasone intravitreal implant 0.7 mg (DEX) as adjunctive therapy to ranibizumab in neovascular age-related macular degeneration (nvAMD). Procedures: This was a 6-month, single-masked, multicenter study. Patients were randomized to DEX implant (n = 123) or sham procedure (n = 120) and received 2 protocol-mandated intravitreal ranibizumab injections. The main outcome measure was injection-free interval to first as-needed ranibizumab injection. Results: DEX increased the injection-free interval versus sham (50th percentile, 34 vs. 29 days; 75th percentile, 85 vs. 56 days; p = 0.016). 8.3% of DEX versus 2.5% of sham-treated patients did not require rescue ranibizumab (p = 0.048). Visual acuity and retinal thickness outcomes were similar in DEX and sham-treated patients. Only reports of conjunctival hemorrhage (18.2 vs. 8.5%) and intraocular pressure elevation (13.2 vs. 4.2%) were significantly different in the DEX versus the sham treatment groups. Conclusion: DEX reduced the need for adjunctive ranibizumab treatment and showed acceptable tolerability in nvAMD patients.

BACKGROUND AND OBJECTIVE: Guidance on the use of corticosteroids in the treatment of diabetic macular edema (DME) is lacking. This study aimed to develop a clinically recommended treatment paradigm for DME with emphasis on the role of corticosteroids. PATIENTS AND METHODS: An expert panel of nine retinal specialists in the United States developed consensus recommendations for DME treatment through a modified Delphi process. RESULTS: The panelists typically use intravitreal injections of vascular endothelial growth factor (VEGF) antagonists as first-line treatment of DME and switch patients with an inadequate response to anti-VEGF therapy (failure of best-corrected visual acuity to improve to 20/40 or better because of edema after three to six monthly injections, or a less-than-50% reduction in excess macular thickness after three to four monthly injections) to intravitreal corticosteroid treatment. CONCLUSION: Intravitreal corticosteroids have a potentially useful role in the treatment of patients with DME who have an inadequate response to intravitreal anti-VEGF therapy. [ Ophthalmic Surg Lasers Imaging Retina. 2017;48:291–301.]

Mitochondrial damage and epigenetic modifications have been implicated in the pathogenesis of Age-related Macular Degeneration (AMD). This study was designed to investigate the effects of AMD/normal mitochondria on epigenetic regulation in human transmitochondrial retinal pigment epithelial (RPE) cells in vitro. Human RPE cybrid cell lines were created by fusing mitochondria-deficient (Rho0) ARPE-19 cells with platelets obtained from either AMD patients (AMD cybrids) or normal subjects (normal cybrids). Therefore, all cybrids had identical nuclei (derived from ARPE-19 cells) but mitochondria derived from either AMD patients or age-matched normal subjects. AMD cybrids demonstrated increased RNA/protein levels for five methylation-related and four acetylation-related genes, along with lower levels of two methylation and three acetylation genes compared to normal cybrids. Demethylation using 5-Aza-2′-deoxycytidine (DAC) led to decreased expression of VEGF-A gene in AMD cells. Trichostatin A (TSA), an HDAC inhibitor, also influenced protein levels of VEGF-A, HIF1α, NFκB, and CFH in AMD cells. Our findings suggest that retrograde signaling leads to mitochondria-nucleus interactions that influence the epigenetic status of the RPE cells and this may help in the identification of future potential therapeutic targets for AMD.

To study the effects of dexamethasone sodium phosphate (Dex) on human trabecular meshwork (HTM) cells in vitro.HTM cells were treated with Dex 2 mg/ml, 1 mg/ml, 0.5 mg/ml, 0.25 mg/ml, 0.1 mg/ml, or 0.05 mg/ml for 24 h. Cell viability was measured by a trypan blue exclusion test. Caspase-3/7, -8, -9 and -12 activities were measured by fluorochrome assays as mean signal intensity (msi) to assess apoptosis. Mitochondrial dehydrogenase activity was determined by a WST assay to quantify mitochondrial damage.Mean cell viabilities of HTM cells exposed to Dex at the higher doses of 2 mg/ml, 1 mg/ml, and 0.5 mg/ml were reduced: 11.9 % ± 3.5 (P 0.001), 31.2 % ± 3.2 (P 0.001), and 76.6 % ± 4.4 (P 0.01). At the lower doses of 0.25 mg/ml, 0.1 mg/ml or 0.05 mg/ml, no significant cell viability reductions were seen: 96.3 % ± 0.7 (P 0.05), 95.3 % ± 2.5 (P 0.05) and 93.8 % ± 2.3 (P 0.05), respectively compared to untreated HTM cells (97.0 % ± 1.9). Caspase-3/7 activity (msi) of HTM cells exposed to Dex 2, 1 or 0.5 mg/ml was 21068 ± 2498 (P 0.001), 26994 ± 3104 (P 0.001) and 20416 ± 1150 (P 0.001) compared to untreated HTM cells 1148 ± 803. Caspase-9 activity (msi) of HTM cells after exposure to Dex 2, 1 or 0.5 mg/ml was 14188 ± 1203 (P 0.001), 13256 ± 1564 (P 0.001) and 15041 ± 1584 (P 0.001) compared to untreated HTM cells 1748 ± 524. The lower doses of Dex did not significantly increase caspase-3/7 or -9 activities. There were no increases for caspase-8 or -12 activities at any of the tested Dex doses. The WST assay showed mitochondrial dehydrogenase activities of 14.3 ± 0.7 (P 0.001), 9.6 ± 0.3 (P 0.001) and 56.0 ± 7.6 (P 0.001) at 2 mg/ml, 1 mg/ml and 0.5 mg/ml Dex compared to untreated HTM cells (186.1 ± 15.0).Dex at 0.25, 0.1 and 0.05 mg/ml clinical dose did not cause significant reduction in cell viability, increased apoptosis, or mitochondrial dysfunction of HTM cells in vitro. At high doses (2, 1 or 0.5 mg/ml) Dex caused apoptosis via mitochondrial pathways.

To compare the durability of Kenalog, Trivaris, Triesence, and compounding pharmacy preservative-free triamcinolone acetonide in pigmented rabbits with syneretic vitreous using direct visualization, pharmacodynamics, and pharmacokinetics.Twenty-five Dutch-belted rabbits were used. Pharmacokinetic experiment: Rabbits were intravitreally injected with one of four 4-mg triamcinolone acetonide formulations. Wide-field imaging was serially performed to document residual drug mass. Pharmacodynamics experiment: Four triamcinolone acetonide groups and one control group received intravitreal recombinant human vascular endothelial growth factor 165 every 2 weeks and were followed with fluorescein angiography to assess vascular endothelial growth factor retinal vasculopathy as a measure of residual steroid effect. Particle size of the formulations was measured with Mastersizer 2000.Remaining triamcinolone acetonide mass after 19 weeks: 12,091 ± 2,512 pixels for the Kenalog group, 1,307.36 ± 695.57 for Trivaris, 5577 ± 1477 for Triesence, and 1,535 ± 329 for compounded preservative-free triamcinolone acetonide. Kenalog suppressed recombinant human vascular endothelial growth factor-induced retinopathy more effectively than the other triamcinolone acetonide groups at Week 39, the final time point assessed. Particle size (90th percentile) was 47 μm for Kenalog, 26 μm for Triesence, and 22 μm for both compounded preservative-free triamcinolone acetonide and Trivaris.Triamcinolone acetonide formulations do not have the same pharmacokinetics/pharmacodynamics. Kenalog has the longest vitreous visibility and durability. Particle size appears to correlate with efficacy and durability.

Background The global prevalence of AMD is projected to be 196 million by the year 2020. Despite substantial progress in the development of new therapies for wet AMD using inhibition of vascular endothelial growth factor (VEGF), the severe visual impairment associated with geographic atrophy in dry AMD remains untreatable. A number of therapeutic options for dry AMD are being developed and are in various stages of clinical trials. Methods Review of literature. Results Enhancers of choroidal blood flow, neuroprotectants and anti-complement factors are the key targets in the research for the treatment of dry AMD. These molecules aim to promote the function of the retinal pigment epithelium and preserve the photoreceptors. Conclusion New molecules are being developed for the treatment of dry AMD, and anti-complement therapy appears to be the most promising among them.

Purpose Variations in mitochondrial DNA (mtDNA) and abnormalities in the complement pathways have been implicated in the pathogenesis of age-related macular degeneration (AMD). This study was designed to determine the effects of mtDNA from AMD subjects on the complement pathway. Methods Transmitochondrial cybrids were prepared by fusing platelets from AMD and age-matched Normal subjects with Rho0 (lacking mtDNA) human ARPE-19 cells. Quantitative PCR and Western blotting were performed to examine gene and protein expression profiles, respectively, of complement markers in these cybrids. Bioenergetic profiles of Normal and AMD cybrids were examined using the Seahorse XF24 flux analyzer. Results Significant decreases in the gene and protein expression of complement inhibitors, along with significantly higher levels of complement activators, were found in AMD cybrids compared to Older-Normal cybrids. Seahorse flux data demonstrated that the bioenergetic profiles for Older-Normal and Older-AMD cybrid samples were similar to each other but were lower compared to Young-Normal cybrid samples. Conclusion In summary, since all cybrids had identical nuclei and differed only in mtDNA content, the observed changes in components of complement pathways can be attributed to mtDNA variations in the AMD subjects, suggesting that mitochondrial genome and retrograde signaling play critical roles in this disease. Furthermore, the similar bioenergetic profiles of AMD and Older-Normal cybrids indicate that the signaling between mitochondria and nuclei are probably not via a respiratory pathway.

PURPOSE To evaluate the efficacy of intravitreal anti-vascular endothelial growth factor monotherapy in the treatment of naive subretinal neovascular membrane (SRNVM) secondary to macular telangiectasia (Mactel) Type 2. METHODS A retrospective chart review of consecutive patients with naive SRNVM secondary to Mactel who were examined between January 2007 and April 2011 was performed. Eyes with diabetic retinopathy, age-related macular degeneration, or any other macular pathology were excluded. Demographic data, medical history, and ocular history were recorded. The mean change in best-corrected visual acuity at the final visit was the primary outcome measure. The mean number of intravitreal injections, retinal thickness on optical coherence tomography, and intraocular pressure were the secondary outcomes. RESULTS A total of 16 eyes of 16 patients were included in the study. Of 16 eyes, 4 were treated with intravitreal ranibizumab monotherapy and 12 with intravitreal bevacizumab monotherapy. The average follow-up duration was 12 months (range, 3-43 months). The mean baseline visual acuity was 0.17 ± 0.16 (Snellen equivalent 20/120) (range, 0.001-0.5), and the mean final visual acuity was 0.27 ± 0.14 (Snellen equivalent 20/70) (range, 0.05-0.66), and this difference was statistically significant (P = 0.02). The mean number of intravitreal injections was 1.9 (range, 1-3), and there were no injection-related complications. CONCLUSION Intravitreal anti-vascular endothelial growth factor monotherapy appears to be effective and safe in treatment-naive SRNVM secondary to Mactel.

To assess the effect of duration of macular edema (ME) on clinical outcomes after treatment with dexamethasone intravitreal implant 0.7 mg (Ozurdex; Allergan, Inc, Irvine, CA) in patients with ME following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).Post hoc analysis of pooled data from 2 randomized, controlled trials.Patients with vision loss resulting from ME of 6 weeks' duration or more after BRVO or CRVO (n = 690).The relationship between ME duration at the time of first treatment and treatment outcomes was assessed using logistic regression. Other factors potentially associated with ME duration or patient outcomes were adjusted for in the analyses.The proportion of patients achieving at least 15 letters improvement in best-corrected visual acuity (BCVA) or at least 200-μm or more reduction in central retinal thickness 6 or 12 months after the first treatment with dexamethasone intravitreal implant 0.7 mg.In the 6-month analysis, each 1-month increase in ME duration was associated with a significantly lower likelihood of achieving a BCVA improvement of 15 letters or more (odds ratio [OR], 0.88; 95% confidence interval [CI], 0.83-0.94; P0.001) or a CRT reduction of 200-μm or more (OR, 0.91; 95% CI, 0.86-0.97; P0.01) 6 months after treatment. In the 12-month analysis, increased ME duration was associated with a significantly lower likelihood of achieving BCVA improvement of 15 letters or more improvement in BCVA (OR, 0.85; 95% CI, 0.76-0.95; P0.01) 12 months after treatment; duration was not significantly associated with the likelihood of a CRT reduction of 200-μm or more at 12 months. In general, the effect of ME duration on outcomes was stronger and statistically significant in BRVO patients, but weaker and not statistically significant in CRVO patients.In eyes with retinal vein occlusion, longer ME duration at the time of first treatment with the dexamethasone intravitreal implant 0.7 mg was associated with a significantly lower likelihood of achieving clinically meaningful improvements in vision or CRT 6 or 12 months after treatment. This suggests that prompt treatment for retinal vein occlusion, particularly BRVO, may be associated with improved clinical outcomes.Proprietary or commercial disclosure may be found after the references.

Purpose: To report the efficacy of 23-gauge (G) pars plana vitrectomy with silicone oil injection in rhegmatogenous retinal detachment. Methods: Retrospective chart review of consecutive patients with retinal detachment who underwent pars plana vitrectomy by one of two surgeons using distinct and consistent methods. All patients undergoing 23-G pars plana vitrectomy did not have scleral buckling, whereas all patients undergoing surgery by 20-G pars plana vitrectomy had additional 240-band encircling scleral buckle. All patients received silicone oil tamponade. Patients with proliferative vitreoretinopathy Grade D, previous retinal detachment surgery, and penetrating eye injury were excluded. The main outcome measure was the final anatomical reattachment rate. The secondary outcome measures were the improvement in visual acuity and recurrence rate of retinal detachment after primary surgery. Results: Eighteen patients in the 23-G group and 21 patients in the 20-G group were analyzed. The mean age of the patients was 48.05 ± 10.37 years and 42.57 ± 17.84 years in the 23-G and 20-G groups, respectively. The mean follow-up duration was 5.9 months (range, 2–12 months) and 6.2 months (range, 4–9 months) in the 23-G and 20-G groups, respectively. The primary reattachment rate was 83.3% (95% confidence interval, 66.11%–100%) in the 23-G group and 86.8% (95% confidence interval, 67.81%–100%); P = 1.00) in 20-G group. The mean preoperative logarithm of the minimum angle of resolution visual acuity was 1.30 ± 0.57 (Snellen equivalent 20/400) in the 23-G group and 1.27 ± 0.70 (Snellen equivalent 20/400) in the 20-G group (P = 0.80). The mean logarithm of the minimum angle of resolution visual acuity at 1 month after the surgery was 0.66 ± 0.25 (Snellen equivalent 20/100) in the 23-G group and 0.77 ± 0.50 (Snellen equivalent 20/120; P = 0.46) in the 20-G group. The visual acuity at the last visit was 0.80 ± 0.52 (20/125) versus 0.65 ± 0.44 (20/100) in the 23-G and 20-G, respectively (P = 0.32). Conclusion: Silicone oil injection with 23-G system is possible and is associated with favorable anatomical success in cases of rhegmatogenous retinal detachment.

Drug delivery into the posterior segment of the eye is complicated by the presence of the blood-ocular barrier. Strategies for delivering drugs to the posterior segment include systemic administration, modification of the blood-eye barrier, and local drug delivery. Recently, new topical treatments have emerged for the treatment of posterior eye disease. Iontophoretic, juxtascleral, and intravitreal routes can be used to achieve therapeutic levels in the posterior segment. Extended-release intravitreal drug delivery systems can achieve sustained therapeutic levels with the goal of providing a prolonged clinical benefit.

A sustained-release biodegradable dexamethasone intravitreal implant (DEX implant) has the potential to become a valuable adjunct to the management of diabetic macular edema. Clinical studies have demonstrated that DEX implant increases visual acuity and decreases macular thickness and vascular leakage in patients with macular edema secondary to diabetic retinopathy, retinal vein occlusion, and noninfectious uveitis. The favorable effects of DEX implant on visual acuity are sustained for up to 6 months. Complications such as increased intraocular pressure and cataract may be less common with DEX implant than with intravitreal injections of triamcinolone acetonide. An applicator is used to place DEX implant into the vitreous cavity in a sutureless, office-based procedure. DEX implant has been approved for the treatment of macular edema following retinal vein occlusion, and for the treatment of intermediate and posterior uveitis. Phase III trials are underway evaluating the long-term efficacy and safety of ...

Purpose To evaluate whether 23-gauge (23 G) pars plana vitrectomy is associated with earlier visual recovery compared with standard 20-gauge (20 G) pars plana vitrectomy. Methods Retrospective chart review of patients who underwent pars plana vitrectomy for various indications was performed. Thirty consecutive eyes in each group of 23-G and 20-G pars plana vitrectomy were analyzed. The mean decimal acuity of each patient was recorded at baseline, Day 1, and Weeks 1 and 6. The visual acuity on postoperative Day 1 and Week 1 was calculated as a proportion of the visual acuity at Week 6. The primary outcome measure was the rate of gain in visual acuity. The secondary outcome measures were intraocular pressure and surgical time. Results The baseline visual acuity between the two groups was similar. The mean visual acuity on Day 1 (0.05 ± 0.09 20 G versus 0.16 ± 0.18 23 G; Snellen equivalent 20/400 versus 20/125; P = 0.004) and Week 1 (0.12 ± 0.20 20 G versus 0.30 ± 0.27 23 G; Snellen equivalent 20/160 versus 20/63; P = 0.002) was significantly better in the 23-G pars plana vitrectomy group. There was no significant difference in best-corrected Snellen visual acuity at Week 6 between the 2 groups. Eighty-three percent of the mean final visual acuity was attained by Week 1 in the 23-G group compared with only 43% in the 20-G group. Conclusion Twenty-three gauge pars plana vitrectomy is associated with faster visual recovery compared with 20-G pars plana vitrectomy.

The use of topical agents poses unique and challenging hurdles for drug delivery. Topical steroids effectively control ocular inflammation, but are associated with the well-recognized dilemma of patient compliance. Although administration of topical antimicrobials as prophylaxis is acceptable among ophthalmologists, this common practice has no sound evidence base. Developing a new antimicrobial agent or delivery strategy with enhanced penetration by considering the anatomical and physiological constraints exerted by the barriers of the eye is not a commonly perceived strategy. Exploiting the permeability of the sclera, subconjunctival routes may offer a promising alternative for enhanced drug delivery and tissue targeting.Ocular drug delivery strategies were reviewed for ocular inflammation and infections clinically adopted for newer class of antimicrobials, which use a multipronged approach to limit risks of endophthalmitis.The analysis substantiates a new transscleral drug delivery therapeutic approach for cataract surgery.A new anti-inflammatory and anti-infective paradigm that frees the patient from the nuisance of topical therapeutics is introduced, opening a large investigative avenue for future improved therapies.

Made available in DSpace on 2020-12-10T20:12:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-02-01 Background: This in vivo study assessed and compared the effectiveness of an aqueous indocyanine green (ICG) formulation (R-ICG) and a lipid ICG formulation (L-ICG) in occluding the rabbit choriocapillaris, and determined the singlet oxygen quantum yields and aggregation properties of both formulations in vitro. Methods: Singlet oxygen production and aggregation were compared. The eye fundus of 30 albino rabbits was irradiated 0-15 min after dye injection using an 810 nm diode laser. Fluorescein angiography and light microscopy were used to evaluate the safety and efficacy of R-ICG and L-ICG. Results: L-ICG decreased the dimerisation constant and the tendency of ICG to form aggregates, and increased the efficiency of ICG in generating singlet oxygen (R-ICG, Phi Delta= 0.120 and L-ICG, Phi Delta= 0.210). Using a 10 mg/kg dose, choriocapillaris occlusion was achieved at a light dose of 35.8 J/cm(2) with L-ICG and 71.6 J/cm(2) with R-ICG with minimal damage to the neurosensory retina. Conclusion: Restrictions to the use of ICG in aqueous solution, low singlet oxygen quantum yields and high aggregation tendency, were overcome with L-ICG. The lower laser irradiance required to obtain choriocapillaris occlusion may suggest that L-ICG is a more potent and selective photosensitiser than R-ICG. Hosp Olhos Araraquara, Retinal Diagnost & Treatment Div, BR-14802530 Araraquara, SP, Brazil Univ Fed Sao Paulo, Paulista Sch Med, Dept Ophthalmol, Sao Paulo, Brazil State Univ Sao Paulo USP Ribeirao Preto, Dept Chem, Riberir Preto, Brazil Univ Calif Irvine, Dept Ophthalmol, Irvine, CA USA State Univ Sao Paulo USP Ribeirao Preto, Dept Chem, Riberir Preto, Brazil

Purpose To determine the association between complement factor H (CFH) polymorphism T1277C (tyrosine-402 → histidine-402) and phenotypic variations of age-related macular degeneration (AMD). Design Cross-sectional observational study. Participants Subjects with dry or wet AMD and a control population consisting of age-matched non-AMD subjects from 2 clinical facilities examined during the period January 1, 1999 through December 31, 2002. Methods Total DNA isolated from the leukocytes of 66 AMD subjects and 58 age-matched control subjects was studied. The CFH gene was amplified by polymerase chain reaction and analyzed by Nla III restriction fragment length analysis. Main Outcome Measures Incidence of CHF polymorphism with the occurrence of AMD. Results Among the AMD patients, 15 had dry and 51 had wet AMD. For the CFH gene, the T1277C variant showed the genotype distribution as CC, TC, and TT. There was a strong association between homozygous C and AMD compared with the control population (odds ratio [OR] = 3.4; 95% confidence interval [CI], 1.32–8.74; P = 0.0053). Furthermore, dry AMD had a stronger association (OR, 8.32; 95% CI, 2.30–30.11; P = 0.001) than wet AMD (OR, 2.49; 95% CI, 0.90–6.84; P = 0.039) compared with the control population. Homozygous T was more prevalent in the control subjects compared with AMD patients (OR, 5; 95% CI, 2.18–11.43; P = 0.00005). Conclusions Complement factor H polymorphism T1277C (tyrosine-402 → histidine-402) is strongly associated with both dry and wet AMD and points to a possible role for inflammation in the pathogenesis of AMD.

Steroids have been extensively used to treat macular edema due to diabetic retinopathy, venous occlusive disease, ocular inflammation and, to a lesser extent, also in some cases of choroidal neovascularization. The various intraocular steroids that have been employed include dexamethasone, triamcinolone and fluocinolone. During the past few years, new drug delivery methods for corticosteroids have been developed and are now part of our therapeutic armamentarium. This chapter provides a brief description of the pharmacology, efficacy and adverse effects associated with the use of steroids in various retinal diseases.

Mitochondrial (mt) DNA can be classified into haplogroups representing different geographic and/or racial origins of populations. The H haplogroup is protective against age-related macular degeneration (AMD), while the J haplogroup is high risk for AMD. In the present study, we performed comparison analyses of human retinal cell cybrids, which possess identical nuclei, but mtDNA from subjects with either the H or J haplogroups, and demonstrate differences in total global methylation, and expression patterns for two genes related to acetylation and five genes related to methylation. Analyses revealed that untreated-H and -J cybrids have different expression levels for nuclear genes (CFH, EFEMP1, VEGFA and NFkB2). However, expression levels for these genes become equivalent after treatment with a methylation inhibitor, 5-aza-2'-deoxycytidine. Moreover, sequencing of the entire mtDNA suggests that differences in epigenetic status found in cybrids are likely due to single nucleotide polymorphisms (SNPs) within the haplogroup profiles rather than rare variants or private SNPs. In conclusion, our findings indicate that mtDNA variants can mediate methylation profiles and transcription for inflammation, angiogenesis and various signaling pathways, which are important in several common diseases.

Retinal astrocytic hamartomas are rare benign tumours that can arise from any location in the retina or from the optic nerve head. Multifocal and bilateral lesions are likely to be associated with tuberous sclerosis and neurofibromatosis1 ,2 but are also often seen in eyes with retinitis pigmentosa.3 ,4 The patient had a family history of second-degree consanguinity in her parents. She had a visual acuity of perception of …

In developed countries, neovascular age-related macular degeneration (AMD) is the leading cause of irreversible central blindness. Although AMD pathogenesis is complex and still not fully understood, many involved mechanisms are already partially known and could be promising targets for future therapies. Currently, anti-VEGF drugs are the standard care of this condition.This review summarizes both the current available and the emerging pharmacological therapies for the management of neovascular AMD. At first, we briefly focused on anti-VEGF compounds that are commonly used. Then, we reviewed the mechanisms of action and potential advantages of new candidate drugs that are being evaluated in clinical trials.Although anti-VEGF drugs have shown mild-term good efficacy and safety profile in the treatment of neovascular AMD, they are far away from being a perfect therapy. Pharmacological research should focus on finding new molecular targets in the AMD pathogenetical pathway and on developing longer lasting agents or new drug delivery systems. Besides the development of new drugs, a better characterization of patients is also needed, taking into account variables such as choroidal neovascularization subtypes and genetic factors, in order to identify a tailored treatment for each patient.

Over the last two decades, there has been an extensive increase in the usage of steroids to treat macular edema due to diabetic retinopathy, venous occlusive disease, ocular inflammation, and also in cases of CNV. Corticosteroids are the one class of agents that act upon most of the multiple processes in the pathophysiology of macular edema.

To prevent indocyanine green (ICG) toxicity during macular hole repair, a surgical technique was designed in which the hole is protected by a viscoelastic material before injecting ICG to stain the internal limiting membrane. The area covered by the viscoelastic material was not stained by ICG. The internal limiting membrane was peeled without difficulty by taking advantage of the ICG stain outlining it. After surgery, all holes closed and the postoperative outcomes were favorable. Only a small amount of residual ICG remained in the macular area. This surgical technique does not interfere with internal limiting membrane peeling and reduces the residual ICG postoperatively. [Ophthalmic Surg Lasers Imaging 2006;37:511-515.] AUTHORS From the Department of Ophthalmology, Fukushima Medical University School of Medicine, Fukushima, Japan. Accepted for publication May 18, 2006. Presented in part at the annual meeting of the Vitreoretina Society of Japan, Fukuoka, Japan, December 13, 2003. Address reprint requests to Masaaki Saito, MD, Department of Ophthalmology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima 960-1295, Japan.

Purpose To compare the safety and efficacy of intravitreal versus posterior Sub–Tenon's capsule injection of triamcinolone acetonide for diffuse diabetic macular edema. Design Prospective, double-masked, randomized controlled trial. Participants Twelve patients (24 eyes) with bilateral diffuse diabetic macular edema. Intervention One eye of each patient was randomly assigned to receive a single 4-mg triamcinolone acetonide intravitreal injection and the fellow eye to receive a 40-mg triamcinolone acetonide posterior Sub–Tenon's capsule injection. Main Outcome Measures Changes in visual acuity and central macular thickness obtained using optical coherence tomography were measured during a 6-month follow-up. Potential treatment complications were monitored, including increases in intraocular pressure (IOP) and cataract progression. Results Both intravitreal and Sub–Tenon's capsule injections of triamcinolone acetonide resulted in significant but transient improvements in central macular thickness. The mean (±standard deviation [SD]) central macular thickness in eyes with intravitreal injection was significantly thinner than in the Sub–Tenon's capsule–injected eyes at 1 month (226.8±41.7 μ m and 431.5±165.8 μ m, respectively; P = 0.002) and 3 months (242.3 ± 93.9 μ m and 364.7±78.2 μ m, respectively; P = 0.005) after triamcinolone acetonide injection. The mean visual acuity (logarithm of the minimum angle of resolution) in the intravitreally injected eyes was significantly better than in the Sub–Tenon's capsule–injected eyes at 3 months post injection (0.832±0.293 and 1.107±0.339, respectively; P = 0.004). Intraocular pressure did not show any significant difference between the 2 forms of triamcinolone acetonide delivery at any follow-up visit, and no eyes had IOPs >25 mmHg. Conclusions The findings from our study neither advocate nor support the use of corticosteroids for the treatment of diabetic macular edema, but do imply that both intravitreal and Sub–Tenon's capsule injections of triamcinolone acetonide may be equally tolerated, with short-term performance clearly favoring the intravitreal (4 mg) more than the SBT capsule (40 mg) route for the anatomic and functional aspects of improvement tested in this investigation.

Purpose: To evaluate the toxicity of indocyanine green (ICG) in combination with light. Methods: Human retinal pigment epithelial cells (ARPE-19) and rat neurosensory retinal cells (R28) were treated with four different concentrations of ICG in combination with light exposure. Cell viability, mitochondrial function, and DNA synthesis were measured. Results: All concentrations of ICG with 10 min of light exposure caused a significant decrease in mitochondrial dehydrogenase activity in R28 and ARPE-19 cells. ICG without light exposure did not decrease mitochondrial dehydrogenase activity. In both cell lines, [3H]thymidine incorporation was increased when treated with ICG with or without light. R28 cells did not show any significant decrease in cell viability. Conclusions: The duration of light was a significant factor in ICG toxicity. ICG needs to be used with caution as it decreases the mitochondrial dehydrogenase activity and increases the DNA synthesis in retinal cells, markers for cell toxicity and dysf...

PURPOSE: To evaluate the safety of intravitreous ovine hyaluronidase for the management of vitreous hemorrhage. DESIGN: Two prospective, randomized, placebo-controlled, double-masked studies. Pooled efficacy data are presented in a companion article in this issue of The Journal. METHODS: Subjects with vitreous hemorrhage > or = 1 month, severe at entry and best corrected visual acuity (BCVA) worse than 20/200 in the study eye were randomized to 7.5 IU, 55 IU, 75 IU ovine hyaluronidase, saline, or no injection. Assessments occurred on day 1, week 1, months 1, 2, 3, 6, and then every 6 months for as long as 32 months. Assessments included history, ocular symptoms, adverse events, BCVA, intraocular pressure, external eye examination, slit-lamp biomicroscopy, fundus examination, B-scan ultrasonography, and fundus photography. RESULTS: Of 1362 subjects in the safety population, 1344 received hyaluronidase or saline and 18 no treatment. Iritis was the most common ocular adverse event, occurring in 33.3%, 62.1%, 58.9%, and 62.1% of saline, 7.5 IU, 55 IU, and 75 IU-treated subjects. In eyes with more than mild iritis, a dose response was observed: 8.9%, 20.2%, 33.7%, and 39.7% of saline, 7.5 IU, 55 IU, and 75 IU-treated subjects, respectively, were noted to have moderate or severe iritis. Retinal detachments (RDs) were reported in 9.5% of study eyes: 26 (6.9%), 22 (11.1%), 35 (9.3%), and 45 (11.5%) in the saline, 7.5 IU, 55 IU, and 75 IU-treated subjects. Overall, 1.8% of study eyes had rhegmatogenous RD: 1.1%, 2.5%, 1.6%, and 2.3% of saline, 7.5, 55, and 75 IU treated subjects. Cataracts occurred similarly across treatment groups. No injection-related infectious endophthalmitis was reported. CONCLUSIONS: No serious safety issues were reported after a single intravitreous injection of ovine hyaluronidase. RD incidence was not statistically different between groups. Iritis manifesting as an acute self limited inflammation was the most common adverse event, occurred in a dose response fashion, but was not noted to result in a serious adverse event in any hyaluronidase treated eye

Background/aims: To determine the potential of an intravitreal sustained release naproxen and 5-fluorouracil (NA/5-FU) codrug for the treatment of experimental proliferative vitreoretinopathy (PVR) in a model for trauma associated tractional retinal detachment (TRD). Methods: Sustained release pellets were prepared by covalently linking naproxen to 5-fluorouracil. Drug release was tested in vitro and toxic effects were evaluated by electroretinography and light microscopy. Traumatic PVR was induced in pigmented rabbits by performing a scleral laceration, followed by repair and intravitreal injection of 0.4 ml of autologous blood. Thirty six eyes were treated with a sustained release implant containing 1.5 mg NA/5-FU as a codrug and 36 control eyes were submitted to surgery alone. Eyes were evaluated for TRD by serial indirect ophthalmoscope examination at different time points followed by postmortem fundus evaluation of the enucleated eye Results: The NA/5-FU pellets were found to provide linear release of 5-FU and naproxen over the 30 day duration of the in vitro release test. Both the severity of PVR grade and the percentage of eyes with moderate or worse tractional detachment were significantly lower in eyes treated with the codrug pellet. There were no drug related toxic effects evident on histopathological or electroretinograph examination of eyes containing the NA/5-FU pellet. Conclusions: The results suggest that this NA/5-FU codrug device effectively inhibits the progression of PVR in a rabbit trauma model that closely resembles PVR in humans. Additional studies to add knowledge to these initial findings and to clarify the potential of the codrug device for the treatment of human PVR are warranted.

● PURPOSE: To evaluate the safety and preliminary efficacy of a novel visual prosthetic device, the Implantable Miniature Telescope, IMT (by Dr Isaac Lipshitz) (IMT), in a phase I trial in patients with significant bilateral central vision impairment from late-stage age-related macular degeneration (AMD). The IMT is designed to reduce the relative size of the scotoma by rendering enlarged (threefold) central visual field images over the central and peripheral retina. ● DESIGN: Prospective, multicenter, open-label clinical trial. ● METHODS: In this prospective, multicenter phase I trial, 14 patients aged 60 or older with bilateral geographic atrophy or disciform scar AMD, cataract, and best-corrected visual acuity (BCVA) between 20/80 and 20/400 had an IMT implanted in one eye. Distance and near BCVA, endothelial cell density, and quality of life, measured as activities of daily life (ADL), were evaluated preoperatively and postoperatively. ● RESULTS: At 12 months, 10 (77%) of 13 patients gained 2 more lines of either distance or near BCVA, and eight (62%) of 13 patients gained 3 or more lines in either distance or near BCVA. Mean endothelial cell density decreased by 13%. All adverse events resolved without sequelae. ADL scores improved in the majority of patients. ● CONCLUSION: The results of this phase I trial support further evaluation of the IMT in a larger study population with late-stage AMD. A phase II/III trial is in progress. (Am J Ophthalmol 2004;137:993‐1001.

PURPOSE To evaluate the onset and duration of improvement in best-corrected visual acuity (BCVA) in eyes treated with dexamethasone intravitreal implant 0.7 mg (DEX implant) for macular edema after branch or central retinal vein occlusion. METHODS Post hoc analysis of data from 2 previously reported multicenter, 6-month, randomized sham-controlled clinical trials. Patients received a single DEX implant (n = 427) or sham procedure (n = 426) in the study eye. The primary endpoint was the percentage of eyes with ≥ 15-letter improvement in BCVA from baseline at postimplant Day 7. RESULTS The baseline mean BCVA was 20/80. At Day 7, 10.3% of DEX implant-treated eyes versus 4.0% of sham-treated eyes (P < 0.001) had ≥ 15-letter improvement in the BCVA, and 27.2% of DEX implant-treated eyes versus 10.6% of sham-treated eyes had ≥ 10-letter improvement (P < 0.001). The mean improvement at Day 7 was 5.3 letters (branch retinal vein occlusion, 5.1; and central retinal vein occlusion, 5.8) with DEX implant and 1.6 letters (branch retinal vein occlusion, 2.3; and central retinal vein occlusion, 0.1) with sham (P < 0.001). The mean time from initial observation of ≥ 15-letter BCVA gain to the last observation of ≥ 15-letter BCVA gain was 70 days. CONCLUSION Dexamethasone intravitreal implant treatment led to improvement in BCVA compared with sham procedure as early as postimplant Day 7. The duration of ≥ 3-line improvement was typically 2 to 3 months.

Human Molecular Genetics, 2014, Vol. 23, No. 13 doi:10.1093/hmg/ddu065 Advance Access published on February 28, 2014 Inherited mitochondrial DNA variants can affect complement, inflammation and apoptosis pathways: insights into mitochondrial –nuclear interactions M. Cristina Kenney 1,2, ∗ , Marilyn Chwa 1 , Shari R. Atilano 1 , Payam Falatoonzadeh 1 , Claudio Ramirez 1 , Deepika Malik 1 , Mohamed Tarek 1 , Javier Ca´ceres-del-Carpio 1 , Anthony B. Nesburn 1,4 , David S. Boyer 5 , Baruch D. Kuppermann 1 , Marquis Vawter 3 , S. Michal Jazwinski 6 , Michael Miceli 6 , Douglas C. Wallace 7 and Nitin Udar 1 Gavin Herbert Eye Institute, 2 Department of Pathology and Laboratory Medicine, 3 Functional Genomics Laboratory, Department of Psychiatry and Human Behavior, University of California Irvine, Irvine, CA, USA, 4 Cedars-Sinai Medical Center, Los Angeles, CA, USA, 5 Retina-Vitreous Associates Medical Group, Beverly Hills, CA, USA, 6 Tulane Center for Aging, Tulane University, New Orleans, LA, USA and 7 Children’s Hospital of Philadelphia, Center for Mitochondrial and Epigenomic Medicine, Philadelphia, PA, USA Received December 17, 2013; Revised February 3, 2014; Accepted February 10, 2014 Age-related macular degeneration (AMD) is the leading cause of vision loss in developed countries. While linked to genetic polymorphisms in the complement pathway, there are many individuals with high risk alleles that do not develop AMD, suggesting that other ‘modifiers’ may be involved. Mitochondrial (mt) haplogroups, defined by accu- mulations of specific mtDNA single nucleotide polymorphisms (SNPs) which represent population origins, may be one such modifier. J haplogroup has been associated with high risk for AMD while the H haplogroup is protective. It has been difficult to assign biological consequences for haplogroups so we created human ARPE-19 cybrids (cyto- plasmic hybrids), which have identical nuclei but mitochondria of either J or H haplogroups, to investigate their effects upon bioenergetics and molecular pathways. J cybrids have altered bioenergetic profiles compared with H cybrids. Q-PCR analyses show significantly lower expression levels for seven respiratory complex genes encoded by mtDNA. J and H cybrids have significantly altered expression of eight nuclear genes of the alternative complement, inflammation and apoptosis pathways. Sequencing of the entire mtDNA was carried out for all the cybrids to identify haplogroup and non-haplogroup defining SNPs. mtDNA can mediate cellular bioenergetics and expression levels of nuclear genes related to complement, inflammation and apoptosis. Sequencing data sug- gest that observed effects are not due to rare mtDNA variants but rather the combination of SNPs representing the J versus H haplogroups. These findings represent a paradigm shift in our concepts of mt–nuclear interactions. INTRODUCTION Mitochondria (mt) are unique organelles that have their own DNA. Human mtDNA is maternally inherited and forms a circle of double-stranded DNA with 16 569 nucleotide pairs. The non-coding mt-Dloop (also called the control region) con- tains 1121 nucleotides important for replication and transcrip- tion. The coding region of mtDNA encodes for 37 genes, including 13 protein subunits essential for oxidative phosphorylation (OXPHOS), 2 ribosomal RNAs and 22 transfer RNAs (1 – 3). The mtDNA can be categorized into haplogroups that are defined by a group of single nucleotide polymorphism (SNP) variants that have accumulated over tens of thousands of years and correspond to various geographic populations. While some studies have shown that certain mtDNA hap- logroups can be either protective or increase risk for human dis- eases (4–10), others report no haplogroup association with diseases (11– 13). However, many of these studies identified To whom correspondence should be addressed at: Gavin Herbert Eye Institute, Discovery Center for Eye Research, University of California Irvine, Hewitt Hall, Room 2028, 843 Health Science Road, Irvine, CA 92697, USA. Tel: +1 9498247603; Fax: +1 9498249626; Email: mkenney@uci.edu # The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Purpose To compare vitrectomy procedures and visualization of posterior segment structures through multifocal silicone intraocular lenses (IOLs) with the same procedures through monofocal silicone IOLs in rabbit eyes. Design Experimental study. Participants Twelve eyes of six rabbits. Methods Each rabbit eye underwent phacoemulsification of the lens and posterior chamber implantation of a silicone multifocal or silicone monofocal IOL. The type of IOL (monofocal vs. multifocal) implanted in the first eye of each rabbit was randomly decided. The fellow eye then received the other IOL type. Vitrectomy procedures were performed through the IOLs by using a flat contact lens (part 1) or wide-angled contact lens (part 2) for visualization through fluid-filled (parts 1 and 2) and air-filled (part 2) eyes. Main outcome measures Image quality, stereopsis, and contrast were subjectively graded on a scale of 0 (none) to 4 (excellent) for each eye by each surgeon. Results In part 1, image quality averaged 4 for the monofocal IOL and 3.6 for the multifocal IOL. Stereopsis averaged 4 for the monofocal IOL and 4 for the multifocal IOL. Contrast averaged 4 for the monofocal IOL and 3.9 for the multifocal IOL. Vitrectomy with retinal surface maneuvers was successfully performed in both pigmented and nonpigmented rabbit eyes through both IOL types. In part 2, image quality, stereopsis, and contrast were rated as 4 for both multifocal and monofocal silicone IOLs. Air-fluid exchange was performed without difficulty. Image quality, stereopsis, and contrast were rated as 4 for air-filled eyes. Conclusions Visualization of posterior segment structures through multifocal silicone IOLs was sufficient for retinal surface maneuvers during vitrectomy procedures in both fluid-filled and air-filled rabbit eyes.

Vitreous from patients with cytomegalovirus (CMV) retinitis was studied in order to identify mutations in the CMV UL97 gene associated with clinical resistance to ganciclovir. Point mutations known to confer resistance (V460, I460, V594, and S595) were found in 6 of 11 study eyes. Rapid genetic screening by restriction enzyme analysis of viral DNA amplified directly from the vitreous was as effective as conventional sequencing in detecting these mutations. Repeat biopsy of 3 eyes revealed no change in the UL97 genotype. The UL97 genotype differed between eyes in 2 of 3 patients with bilateral, clinically resistant CMV retinitis. In summary, resistance mutations of the CMV UL97 gene are found in the vitreous of some, but not all, eyes with CMV retinitis that have not responded to ganciclovir therapy. These mutations can differ between eyes in patients with bilateral disease and can be rapidly detected using restriction digest analysis of polymerase chain reaction-amplified viral DNA.

Dexamethasone palmitate (DXP) is a lipophilic prodrug of dexamethasone (DXM), a potent corticosteroid used to treat a variety of ophthalmic diseases. The aim of the study was to characterize the sustained release capacity (in rabbit), efficacy (in rat and rabbit), and safety (in rabbit, cat, and minipig) of intravitreal (IVT) DXP emulsions in preclinical models.Oil-in-water emulsions of DXP were administered by IVT injections in rats, rabbits, cats, or minipigs. Efficacy was assessed in rabbits by the inhibition of VEGF-induced vascular leakage and in rats by inhibition of laser-induced choroidal neovascularization. Concentrations of DXP and DXM in aqueous humor, vitreous, retina, choroid, and blood were determined to characterize the ocular and systemic pharmacokinetic (PK) profile. Complete ophthalmic examinations (indirect ophthalmoscopy, slit-lamp biomacroscopy, electroretinography, tonometry) were performed to assess the ocular safety of IVT DXP doses up to 2,600 μg in minipig, followed by histopathologic examinations. A validated feline model of DXM-induced elevated intraocular pressure (IOP) was used to assess the ocular hypertensive impact (i.e., the safety) of an IVT injection of DXP emulsion.Rat and rabbit efficacy data demonstrated that IVT injections of DXP emulsions were effective. Rabbit PK data demonstrated that following a single 1,280 μg IVT injection resulted in sustained DXM levels in the retina and choroid (1,179.6 and 577.7 ng/g with a half-life of 189 and 103 days, respectively) sufficient to inhibit VEGF-induced vascular hyper-permeability for up to 9 months. No adverse ocular findings were observed in the rabbit at the 1,280 μg DXP dose. Plasma levels of DXP and DXM were close to the lower limit of quantification (0.5 ng/mL). In minipigs, no systemic effects were observed at a dose up to 2,600 μg DXP. In steroid responsive cats, IVT DXP emulsions increased IOP to a lesser extent than triamcinolone acetonide with a more rapid return to basal levels and no evidence of cataract formation.IVT injections of DXP emulsions were well tolerated and shown to be efficacious for the sustained release of the drug, with the potential to control vascular leakage up to 9 months following a single IVT injection. These data suggest that IVT injections of DXP emulsions could be a safe and effective alternative IVT drug delivery vehicle for corticosteroid to treat back of the eye diseases complicated by macular edema.

Purpose: To evaluate the effect of bevacizumab on the mitochondrial function of human retinal pigment epithelial (ARPE-19), rat neurosensory retinal (R28) and human microvascular endothelial (HMVEC) cells in culture. Materials and Methods: ARPE-19 and R28 cells were treated with 0.125, 0.25, 0.50 and 1 mg/ml of bevacizumab. The HMVEC cultures were treated with 0.125, 0.25, 0.50 and 1 mg/ml of bevacizumab or 1 mg/ml of immunoglobulin G (control). Mitochondrial function assessed by mitochondrial dehydrogenase activity (MDA) was determined using the WST-1 assay. Results: Bevacizumab doses of 0.125 to 1 mg/ml for 5 days did not significantly affect the MDA of ARPE-19 cells. Bevacizumab treatment at 0.125 and 0.25 mg/ml (clinical dose) did not significantly affect the MDA of R28 cells; however, 0.50 and 1 mg/ml doses significantly reduced the R28 cell mitochondrial function. All doses of bevacizumab significantly reduced the MDA of proliferating and non-proliferating HMVEC. Conclusion: Bevacizumab exposure for 5 days was safe at clinical doses in both ARPE-19 and R28 retinal neurosensory cells in culture. By contrast, bevacizumab exposure at all doses show a significant dose-dependent decrease in mitochondrial activity in both the proliferating and non-proliferating HMVEC in vitro. This suggests a selective action of bevacizumab on endothelial cells at clinical doses.

Mitochondrial DNA Variants Mediate Energy Production and Expression Levels for CFH, C3 and EFEMP1 Genes: Implications for Age-Related Macular Degeneration M. Cristina Kenney 1 *, Marilyn Chwa 1 , Shari R. Atilano 1 , Janelle M. Pavlis 1 , Payam Falatoonzadeh 1 , Claudio Ramirez 1 , Deepika Malik 1 , Tiffany Hsu 1 , Grace Woo 1 , Kyaw Soe 1 , Anthony B. Nesburn 1,2 , David S. Boyer 3 , Baruch D. Kuppermann 1 , S. Michal Jazwinski 4 , Michael V. Miceli 4 , Douglas C. Wallace 5 , Nitin Udar 1 1 Gavin Herbert Eye Institute, University of California Irvine, Irvine, California, United States of America, 2 Cedars-Sinai Medical Center, Los Angeles, California, United States of America, 3 Retina-Vitreous Associates Medical Group, Beverly Hills, California, United States of America, 4 Tulane Center for Aging and Department of Medicine, Tulane University, New Orleans, Louisiana, United States of America, 5 Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, United States of America Abstract Background: Mitochondrial dysfunction is associated with the development and progression of age-related macular degeneration (AMD). Recent studies using populations from the United States and Australia have demonstrated that AMD is associated with mitochondrial (mt) DNA haplogroups (as defined by combinations of mtDNA polymorphisms) that represent Northern European Caucasians. The aim of this study was to use the cytoplasmic hybrid (cybrid) model to investigate the molecular and biological functional consequences that occur when comparing the mtDNA H haplogroup (protective for AMD) versus J haplogroup (high risk for AMD). Methodology/Principal Findings: Cybrids were created by introducing mitochondria from individuals with either H or J haplogroups into a human retinal epithelial cell line (ARPE-19) that was devoid of mitochondrial DNA (Rho0). In cybrid lines, all of the cells carry the same nuclear genes but vary in mtDNA content. The J cybrids had significantly lower levels of ATP and reactive oxygen/nitrogen species production, but increased lactate levels and rates of growth. Q-PCR analyses showed J cybrids had decreased expressions for CFH, C3, and EFEMP1 genes, high risk genes for AMD, and higher expression for MYO7A, a gene associated with retinal degeneration in Usher type IB syndrome. The H and J cybrids also have comparatively altered expression of nuclear genes involved in pathways for cell signaling, inflammation, and metabolism. Conclusion/Significance: Our findings demonstrate that mtDNA haplogroup variants mediate not only energy production and cell growth, but also cell signaling for major molecular pathways. These data support the hypothesis that mtDNA variants play important roles in numerous cellular functions and disease processes, including AMD. Citation: Kenney MC, Chwa M, Atilano SR, Pavlis JM, Falatoonzadeh P, et al. (2013) Mitochondrial DNA Variants Mediate Energy Production and Expression Levels for CFH, C3 and EFEMP1 Genes: Implications for Age-Related Macular Degeneration. PLoS ONE 8(1): e54339. doi:10.1371/journal.pone.0054339 Editor: Walter Lukiw, Louisiana State University Health Sciences Center, United States of America Received October 1, 2012; Accepted December 10, 2012; Published January 24, 2013 Copyright: s 2013 Kenney et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding provided by The Discovery Eye Foundation www.discoveryeye.org, Lincy Foundation lincyinstitute.unlv.edu/lincy.html, Beckman Macular Research Initiative www.beckmanmacular.org, The Henry Guenther Foundation, Polly and Michael Smith Foundation, Research to Prevent Blindness Foundation www.rpbusa.org, and the National Institute on Aging (AG006168). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: mkenney@uci.edu specific SNP variants that have accumulated over tens of thousands of years and correspond to different geographic populations of the world. The H haplogroup is the most common European haplogroup, while the J haplogroup originates from the Northern European region and is defined by SNP variants that are associated with heat production as an adaptation to colder climates [4]. The mtDNA plays an important role in aging and diseases [4– 6]. Specific haplogroups are associated with a variety of eye diseases including age-related macular degeneration (AMD) [7– 10], diabetic retinopathy [11], pseudoexfoliation glaucoma [12,13], primary open-angle glaucoma [14], keratoconus [15], multiple sclerosis-related optic neuritis [16,17], and Leber Introduction Mitochondria provide critical cellular energy using the tricar- boxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and beta-oxidation of fatty acids for metabolism, cell division, production of reactive oxygen species (ROS), and apoptosis. Human mitochondrial (mt) DNA forms a circle of double stranded DNA with 16,569 nucleotide pairs. The non-coding mtDNA Dloop contains 1121 nucleotides and is important for replication and transcription. The coding region of mtDNA encodes for 37 genes including 13 protein subunits essential for OXPHOS, 2 ribosomal RNAs, and 22 transfer RNAs [1–3]. The mtDNA can be categorized into haplogroups that are defined by a set of PLOS ONE | www.plosone.org January 2013 | Volume 8 | Issue 1 | e54339

The vitreous may play an important role in the pathogenesis of various retinal disorders. Pharmacologic vitreolysis uses intravitreal pharmacologic agents to provide liquefaction of the vitreous and complete vitreoretinal separation. Ocriplasmin, a genetically engineered version of plasmin, has been shown in clinical trials to be able to safely release vitreomacular adhesion and close Stage 2 macular holes in a significant number of patients. Advancements in the development of this safe and effective method of vitreolysis have provided an alternative, nonsurgical treatment option to physicians who manage these patients. A roundtable of clinical investigators convened to discuss and summarize recent progress in pharmacologic vitreolysis. Preclinical studies, and efficacy and safety data from controlled clinical trials of ocriplasmin were presented and discussed. Case studies were then presented to provide an opportunity for experts to reveal their specific thoughts regarding ocriplasmin for the treatment of vitreomacular adhesion and resulting vitreomacular traction and macular holes, based on their own interpretation of current clinical data and experience.

Purpose To evaluate Ozurdex (dexamethasone intravitreal implant [DEX implant]; Allergan, Inc, Irvine, CA) 0.7 mg combined with laser photocoagulation compared with laser alone for treatment of diffuse diabetic macular edema (DME). Design Randomized, controlled, multicenter, double-masked, parallel-group, 12-month trial. Participants Two hundred fifty-three patients with retinal thickening and impaired vision resulting from diffuse DME in at least 1 eye (the study eye) were enrolled. Intervention Patients were randomized to treatment in the study eye with DEX implant at baseline plus laser at month 1 (combination treatment; n = 126) or sham implant at baseline and laser at month 1 (laser alone; n = 127) and could receive up to 3 additional laser treatments and 1 additional DEX implant or sham treatment as needed. Main Outcome Measures The primary efficacy variable was the percentage of patients who had a 10-letter or more improvement in best-corrected visual acuity (BCVA) from baseline at month 12. Other key efficacy variables included the change in BCVA from baseline and the area of vessel leakage evaluated with fluorescein angiography. Safety variables included adverse events and intraocular pressure (IOP). Results The percentage of patients who gained 10 letters or more in BCVA at month 12 did not differ between treatment groups, but the percentage of patients was significantly greater in the combination group at month 1 ( P P = 0.007). In patients with angiographically verified diffuse DME, the mean improvement in BCVA was significantly greater with DEX implant plus laser treatment than with laser treatment alone (up to 7.9 vs. 2.3 letters) at all time points through month 9 ( P ≤0.013). Decreases in the area of diffuse vascular leakage measured angiographically were significantly larger with DEX implant plus laser treatment through month 12 ( P ≤0.041). Increased IOP was more common with combination treatment. No surgeries for elevated IOP were required. Conclusions There was no significant between-group difference at month 12. However, significantly greater improvement in BCVA, as demonstrated by changes from baseline at various time points up to 9 months and across time based on the area under the curve analysis, occurred in patients with diffuse DME treated with DEX implant plus laser than in patients treated with laser alone. Financial Disclosure(s) Proprietary or commercial disclosure may be found after the references.

Macular edema is one of the leading causes of vision loss among patients with retinal vein occlusion, diabetic retinopathy, and posterior chamber inflammatory disease. However, the treatment of macular edema is considerably limited by the difficulty in delivering effective doses of therapeutic agents into the vitreous cavity. In recent years, the development of a sustained-release dexamethasone intravitreal implant (Ozurdex®) has enabled more controlled drug release at a stable rate over a long period of time, with a potentially lower rate of adverse events. Clinical studies indicate that this dexamethasone implant is a promising new treatment option for patients with persistent macular edema resulting from retinal vein occlusion, diabetic retinopathy, and uveitis or Irvine-Gass syndrome. © 2011 Herrero-Vanrell et al.

PURPOSE The purpose of this study was to evaluate the correlation between best-corrected visual acuity (BCVA) and macular thickness in patients with persistent macular edema treated with a dexamethasone intravitreal drug delivery system (dexamethasone DDS). METHODS In a randomized, multicenter, controlled, parallel-group, dose-ranging study, patients with macular edema lasting at least 90 days despite treatment were randomized to observation or treatment with 350- or 700-microg dexamethasone DDS. Macular thickness was assessed in 80 patients using optical coherence tomography. Best-corrected visual acuity was measured using Early Treatment Diabetic Retinopathy Study methodology. RESULTS At baseline, macular thickness was significantly inversely correlated with BCVA (r = -0.406, P < 0.001). Patients treated with 350- or 700-microg dexamethasone DDS showed a significant decrease in macular thickness from baseline to Day 90 (P = 0.002). In the 700-microg dexamethasone DDS treatment group, there was a modest inverse correlation between changes in macular thickness from baseline to Day 90 and improvement in BCVA (r = -0.530, P = 0.009). In the 350-microg dexamethasone DDS treatment group, the correlation was weaker and not statistically significant (r = -0.206, P = 0.304). CONCLUSION The correlation between baseline BCVA and macular thickness in patients with persistent macular edema was modest. Improvement in BCVA after treatment with 700-microg dexamethasone DDS was consistent with changes in macular thickness measured using optical coherence tomography.

Background: Full-thickness macular holes generally cause a significant reduction in visual acuity, due in part to a rim of surrounding neurosensory retinal detachment and retinal thickening. Recent studies have suggested that flattening of this narrow rim of neurosensory detachment can result in improved visual acuity. However, the ability to flatten the neurosensory detachment is limited using current surgical techniques. Methods: Transforming growth factor-β 2 (TGF-β 2 ) is a recently discovered potent stimulator of wound healing. The authors, therefore, performed a prospective randomized study of 60 patients to determine if the local application of TGF-β 2 to the edge of the macular hole can reproducibly induce flattening of the surrounding neurosensory detachment. The results of a study designed to determine the effect of a pars plana vitrectomy, fluid-gas exchange, and intravitreal instillation of TGF-β 2 in eyes with a fullthickness macular hole and reduced visual acuity are reported. Results: After treatment, visual acuity improved 2 lines or more in 5 of 11 eyes treated with 70 ng, in 4 of 12 eyes treated with 330 ng, and in 10 of 11 eyes treated with 1330 ng of TGF-β 2 . In some eyes, hyaluronic acid was added. In these cases, visual acuity improved 2 lines or more in 0 of 9 eyes treated with 70 ng TGF-β 2 , in 2 of 8 eyes treated with 330 ng, and in 4 of 9 eyes treated with 1330 ng. Conclusion: Logistic regression analysis demonstrated a statistically significant beneficial effect of TGF-β 2 on visual improvement ( P = 0.003).

The most significant obstacle to the combination of drug therapies in age-related macular degeneration (AMD) may be drug delivery. Although the posterior of the eye can be reached by intravitreal injections and implants, AMD is a chronic disease process that is likely to require prolonged or indefinite exposure to antiproliferative agents. In addition to the difficulty of repeat dosing in the vitreal space, ocular anatomy prohibits substantial drug volumes, a limitation further compounded when combining two or more agents. With low penetration to target areas of AMD, pathophysiology, and risk of significant systemic toxicity through systemic drug delivery, innovative strategies for introducing agents to their site of action may be the critical component of improved outcomes.