Carl D. Regillo

Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt's macular dystrophy: follow-up of two open-label phase 1/2 studies

BACKGROUNDnSince they were first derived more than three decades ago, embryonic stem cells have been proposed as a source of replacement cells in regenerative medicine, but their plasticity and unlimited capacity for self-renewal raises concerns about their safety, including tumour formation ability, potential immune rejection, and the risk of differentiating into unwanted cell types. We report the medium-term to long-term safety of cells derived from human embryonic stem cells (hESC) transplanted into patients.nnnMETHODSnIn the USA, two prospective phase 1/2 studies were done to assess the primary endpoints safety and tolerability of subretinal transplantation of hESC-derived retinal pigment epithelium in nine patients with Stargardts macular dystrophy (age >18 years) and nine with atrophic age-related macular degeneration (age >55 years). Three dose cohorts (50,000, 100,000, and 150,000 cells) were treated for each eye disorder. Transplanted patients were followed up for a median of 22 months by use of serial systemic, ophthalmic, and imaging examinations. The studies are registered with ClinicalTrials.gov, numbers NCT01345006 (Stargardts macular dystrophy) and NCT01344993 (age-related macular degeneration).nnnFINDINGSnThere was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. 13 (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16-25 points 3-12 months after transplantation in patients with atrophic age-related macular degeneration and 8-20 points in patients with Stargardts macular dystrophy.nnnINTERPRETATIONnThe results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that hESC-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.nnnFUNDINGnAdvanced Cell Technology.

Genetic variants near TIMP3 and high-density lipoprotein–associated loci influence susceptibility to age-related macular degeneration

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10−75), ARMS2 (P < 10−59), C2/CFB (P < 10−20), C3 (P < 10−9), and CFI (P < 10−6). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10−11), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 × 10−7; CETP, P = 7.4 × 10−7) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL (P = 3.0 × 10−3) and ABCA1 (P = 5.6 × 10−4). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

A Treat and Extend Regimen Using Ranibizumab for Neovascular Age-Related Macular Degeneration: Clinical and Economic Impact

PURPOSEnTo evaluate the visual outcome, number of injections, and direct medical cost of a treat and extend regimen (TER) in managing neovascular age-related macular degeneration (nAMD) with intravitreal ranibizumab.nnnDESIGNnRetrospective, interventional, consecutive case series.nnnPARTICIPANTSnNinety-two eyes of 92 patients met the entry criteria from May 2006 to May 2008.nnnMETHODSnAll patients with treatment-naïve nAMD were treated monthly until no intraretinal or subretinal fluid was observed on optical coherence tomography (OCT). The treatment intervals were then sequentially lengthened by 2 weeks until signs of exudation recurred. The interval was individualized for each patient in an attempt to maintain an exudation-free macula.nnnMAIN OUTCOME MEASURESnChange from baseline visual acuity, proportion of eyes losing < 3 lines and gaining ≥ 3 lines at 1 year of follow-up, annual mean number of injections, change from baseline OCT central retinal thickness (CRT), maximum period of extension, and adverse ocular and systemic events.nnnRESULTSnThe mean follow-up was 1.52 years. Mean Snellen visual acuity improved from 20/135 at baseline to 20/77 at 1 year follow-up (P < 0.001) and 20/83 at 2 years follow-up (P = 0.002). The proportion of eyes that lost < 3 Snellen visual acuity lines at final follow-up was 96% and the proportion that gained ≥ 3 Snellen visual acuity lines was 32%. The mean OCT CRT decreased from 303 μm at baseline to 238 μm at 1 year follow-up (P < 0.001). The mean number of injections over the first year and between years 1 and 2 was 8.36 and 7.45, respectively. The mean maximum period of extension was 79.9 days. No adverse ocular or systemic events were reported during the follow-up period. The direct annual medical cost per patient was

Indocyanine green angiography and occult choroidal neovascularization

16,114.52 for the TER. The direct annual medical cost per patient ranged from

Bevacizumab for Neovascular Age-Related Macular Degeneration Using a Treat-and-Extend Regimen: Clinical and Economic Impact

15,880.07 to

Repair of Retinitis-related Retinal Detachments With Silicone Oil in Patients With Acquired Immunodeficiency Syndrome

28,314.16 based on previous clinical trial protocols.nnnCONCLUSIONSnEyes with nAMD experienced significant visual improvement when managed with intravitreal ranibizumab using a TER. This treatment approach also was associated with significantly fewer patient visits, injections, and direct annual medical cost compared with monthly injections such as in the phase III clinical trials.nnnFINANCIAL DISCLOSURE(S)nProprietary or commercial disclosure may be found after the references.

Successful scleral buckling procedures decrease central retinal artery blood flow velocity

PURPOSEnTo evaluate the use of digital indocyanine green (ICG) angiography as an adjunct to fluorescein angiography in the diagnosis and treatment of ill-defined choroidal neovascularization (CNV) associated with age-related macular degeneration (AMD).nnnMETHODSnThe authors retrospectively reviewed all ICG angiograms performed at Wills Eye Hospital from March to July 1992. Included in this study were all cases with exudative manifestations of AMD in which fluorescein angiography showed ill-defined CNV. The initial ICG findings and the clinical outcome of both treated and untreated cases were evaluated through 6 months of follow-up.nnnRESULTSnOf the 101 eligible cases, ICG angiography at presentation demonstrated well-defined hyperfluorescence in 40 cases (group 1), ill-defined hyperfluorescence in 43 cases (group 2), mixed pattern of well- and ill-defined hyperfluorescence in 14 cases (group 3), and no abnormalities in 4 cases (group 4). Approximately one half of the cases with well-defined ICG hyperfluorescence (21% of the total) had only extrafoveal changes. Laser photocoagulation treatment based solely on ICG angiogram findings was performed in 19 group 1 cases (extrafoveal hyperfluorescent foci only) and in 8 group 3 cases, with treatment in both groups being directed only to areas of well-defined hyperfluorescence. Successful treatment was achieved in 12 (63%) of 19 cases and in 2 (25%) of 8 cases, respectively. There was a strong correlation between post-treatment persistence or recurrence of ICG hyperfluorescence and treatment failure.nnnCONCLUSIONSnIndocyanine green angiography is a valuable diagnostic adjunct to fluorescein angiography in evaluating occult CNV in AMD. In this series, well-defined, extrafoveal ICG hyperfluorescence was identified in 21% of the cases, and preliminary, short-term results suggest that ICG-guided laser treatment is promising in this subgroup.

Analysis of Six Genetic Risk Factors Highly Associated with AMD in the Region Surrounding ARMS2 and HTRA1 on Chromosome 10, Region q26

PURPOSEnTo evaluate the visual outcomes, number of injections, and direct medical cost of a treat-and-extend regimen in managing neovascular age-related macular degeneration with intravitreal bevacizumab.nnnDESIGNnRetrospective, interventional, consecutive case series.nnnMETHODSnSeventy-four eyes of 73 patients with treatment-naïve neovascular age-related macular degeneration from a single clinical practice were treated monthly with intravitreal bevacizumab until no intraretinal or subretinal fluid was observed on optical coherence tomography. The treatment intervals then were lengthened sequentially by 2 weeks until signs of exudation recurred and then were reduced accordingly to maintain an exudation-free macula. Main outcomes measured included mean change from baseline visual acuity, proportion of eyes losing fewer than 3 and gaining 3 or more Snellen visual acuity lines at 1 year of follow-up, annual mean number of injections, optical coherence tomography mean central retinal thickness change from baseline, mean maximum period of extension, adverse events, and mean direct annual medical cost.nnnRESULTSnThe mean follow-up period was 1.41 years. Mean Snellen visual acuity improved from 20/230 at baseline to 20/109 at 12 months (P < .001) and 20/106 at 24 months (P < .001). The mean number of injections over the first year was 7.94. The mean optical coherence tomography central retinal thickness decreased from 316 to 239 μm at 12 months (P < .001). The mean direct medical cost over the first year was

Efficacy of intravitreal ocriplasmin on vitreomacular traction and full-thickness macular holes.

3493.85.nnnCONCLUSIONSnEyes with neovascular age-related macular degeneration experienced significant visual improvements on average when managed with intravitreal bevacizumab using a treat-and-extend regimen with fewer patient visits and injections along with lower costs compared with a fixed, monthly dosing regimen.

Comparison of Aflibercept, Bevacizumab, and Ranibizumab for Treatment of Diabetic Macular Edema: Extrapolation of Data to Clinical Practice.

To provide prompt visual rehabilitation and to reduce the need for repeated operations, we performed vitrectomy with silicone oil tamponade in 16 consecutive eyes with retinal detachments related to cytomegalovirus retinitis and acute retinal necrosis in 13 patients with acquired immunodeficiency syndrome. In all 16 eyes (100%), retinas were reattached with one operation. Preservation of ambulatory vision was achieved in six of eight eyes (75%; mean follow-up, 14.6 weeks). No patient with hand motion visual acuity or worse preoperatively recovered ambulatory vision. Visual acuity recovery was limited by optic nerve disease in five eyes (31%). Silicone oil-related side effects did not adversely affect visual outcome in any eye. Six patients (46%) have since died (mean, 4.4 months postoperatively). These data indicated that successful surgical repair of these detachments can be consistently achieved with this approach. The prognosis for ambulatory vision is strongly related to preoperative visual acuity.