Treating patients with geographic atrophy: are we there yet?
Ontology highlight
ABSTRACT:
SUBMITTER: Antonio-Aguirre B
PROVIDER: S-EPMC10658861 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:PurposeGeographic atrophy (GA) is a late-stage form of age-related macular degeneration (AMD) characterized by the expansion of atrophic lesions in the outer retina. There are currently no approved pharmacological treatments to prevent or slow the progression of GA. This review describes the progression and assessment of GA, predictive imaging features, and complement-targeting investigational drugs for GA.MethodsA literature search on GA was conducted.ResultsExpansion of atrophic lesions in patients with GA is associated with a decline in several measures of visual function. GA lesion size has been moderately associated with measures obtained through microperimetry, whereas GA lesion size in the 1-mm diameter area centered on the fovea has been associated with visual acuity. Optical coherence tomography (OCT) can provide 3-dimensional quantitative assessment of atrophy and is useful for identifying early atrophy in GA. Features that have been found to predict the development of GA include certain drusen characteristics and pigmentary abnormalities. Specific OCT features, including hyper-reflective foci and OCT-reflective drusen substructures, have been associated with AMD disease progression. Lesion characteristics, including focality, regularity of shape, location, and perilesional fundus autofluorescence patterns, have been identified as predictors of faster GA lesion growth. Certain investigational complement-targeting drugs have shown efficacy in slowing the progression of GA.ConclusionGA is a progressive disease associated with irreversible vision loss. Therefore, the lack of treatment options presents a significant unmet need. OCT and drugs under investigation for GA are promising future tools for disease management.
| S-EPMC10198833 | biostudies-literature
Project description:Early age-related macular degeneration (AMD) is characterized by degeneration of the choriocapillaris, the vascular supply of retinal photoreceptor cells. We assessed vascular loss during disease progression in the choriocapillaris and larger vessels in the deeper choroid. Human donor maculae from controls (n = 99), early AMD (n = 35), or clinically diagnosed with geographic atrophy (GA; n = 9, collected from outside the zone of retinal pigment epithelium degeneration) were evaluated using Ulex europaeus agglutinin-I labeling to discriminate between vessels with intact endothelial cells and ghost vessels. Morphometric analyses of choriocapillaris density (cross-sectional area of capillary lumens divided by length) and of vascular lumen/stroma ratio in the outer choroid were performed. Choriocapillaris loss was observed in early AMD (Bonferroni-corrected P = 0.024) with greater loss in GA (Bonferroni-corrected P < 10-9), even in areas of intact retinal pigment epithelium. In contrast, changes in lumen/stroma ratio in the outer choroid were not found to differ between controls and AMD or GA eyes (P > 0.05), suggesting choriocapillaris changes are more prevalent in AMD than those in the outer choroid. In addition, vascular endothelial growth factor-A levels were negatively correlated with choriocapillaris vascular density. These findings support the concept that choroidal vascular degeneration, predominantly in the microvasculature, contributes to dry AMD progression. Addressing capillary loss in AMD remains an important translational target.
| S-EPMC6616998 | biostudies-literature
Project description:ImportanceIntraocular pressure (IOP) elevations of clinical relevance have been observed after the commonly used 0.05-mL volume for intravitreous injections. However, more recently approved intravitreous agents involve volumes from 0.07 to 0.1 mL. It is not well established whether repeated 0.1-mL intravitreous injections may result in IOP-related complications.ObjectiveTo investigate the effect of 1 year of repeated 0.1-mL intravitreous injections on IOP outcomes.Design, setting, and participantsThis study was a post hoc analysis of 2 clinical trials investigating the IOP safety of intravitreous lampalizumab on geographic atrophy secondary to age-related macular degeneration. Both trials were conducted between 2014 and 2018 and recruited participants who were 50 years or older and had bilateral geographic atrophy. This post hoc analysis was performed between 2018 and 2022.InterventionsIntravitreous lampalizumab, 0.1 mL, every 4 weeks; lampalizumab, 0.1 mL, every 6 weeks; or sham procedure every 4 weeks or 6 weeks for 48 weeks.Main outcomes and measuresIOP changes in the 4-week-frequency study arms and ocular adverse events to week 48 in all arms. The hypothesis for this analysis was formulated after data collection.ResultsAmong a total of 1851 participants, there was no change in mean pre-injection IOP values through 48 weeks in either arm. The adverse events glaucoma and ocular hypertension were reported for 1.8% of participants treated with lampalizumab and 1.6% of those in the sham arm.Conclusions and relevanceOver 1 year, IOP increases were rare and did not affect treated participants more frequently than sham arm participants. These findings support the low risk of persistent IOP increases, on average, of intravitreous 0.1-mL injection volumes administered for 1 year in a manner similar to that performed in these clinical trials. These results may be valuable in the design of future therapeutic trials considering this volume for injections particularly as more recently approved agents use volumes of 0.07 to 0.1 mL.Trial registrationClinicalTrials.gov Identifiers: NCT02247479 and NCT02247531.
| S-EPMC11190824 | biostudies-literature
Project description:The Gut Microbiome in Geographic Atrophy
| PRJEB74776 | ENA
Project description:PurposeTo investigate the association between rim area focal hyperautofluorescence (RAFH) signals and geographic atrophy (GA) growth rates, as well as the impact of oral metformin on the longitudinal change of RAFH.DesignSecondary analysis of a randomized controlled trial.ParticipantsSeventy-one eyes from 44 participants with GA and ≥6 months of follow-up in the METformin for the MINimization of geographic atrophy progression study.MethodsFundus autofluorescence images were captured using a 488 nm excitation wavelength. Two masked graders identified and measured RAFH lesions using proprietary semiautomatic segmentation software and ImageJ. We calculated RAFH by dividing the areas of hyperautofluorescence within a 450-μm rim circumscribing the GA by the total area enclosed within this rim.Main outcome measuresLongitudinal changes in RAFH and GA area.ResultsBaseline RAFH was positively associated with the baseline square root of GA area 0.065/year (P < 0.001). In the entire study cohort, higher baseline RAFH was associated with a faster GA area growth rate in mm2/year (Spearman's ρ = 0.53; P < 0.001). The association became weaker in square root-transformed GA area growth (ρ = 0.19, P = 0.11) and perimeter-adjusted GA growth rate (ρ = 0.28, P = 0.02), achieving statistical significance only in the latter. When this analysis was stratified into 3 baseline GA tertiles, the first and second tertiles showed weak to moderate association with statistical significance in all 3 modes of GA growth rates. Rim area focal hyperautofluorescence increased slightly but significantly over time at 0.020/year (P < 0.01). Rim area focal hyperautofluorescence increased slightly but significantly over time at 0.020/year (P < 0.01). The use of oral metformin was not significantly associated with the change in RAFH over time compared with the observation group (0.023/year vs. 0.016/year; P = 0.29).ConclusionsIncreased baseline RAFH is associated with faster GA area progression. However, the effect size of this association may depend on the baseline GA lesion size such that small to medium-sized GA lesions display this relationship regardless of the mode of the calculation of GA growth rate.Financial disclosuresProprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
| S-EPMC11585696 | biostudies-literature
Project description:Intravitreally administered lampalizumab is an investigational complement inhibitor directed against complement factor D (CFD) for the treatment of geographic atrophy (GA) secondary to age-related macular degeneration. We sought to develop an integrated ocular and systemic pharmacokinetic/pharmacodynamic model for lampalizumab in patients with GA using the data from the clinical phase I and II studies. The kinetics of lampalizumab and CFD disposition were well described by the combined ocular/serum target-mediated drug disposition model using a quasi-steady-state approximation. This model takes into account the drug, target, and drug-target complex clearance, their transfer rates between ocular and serum compartments, and turnover kinetics of CFD. The constructed model provided a prediction of target occupancy in ocular tissues and supported that the two dosing regimens (10 mg q4w and 10 mg q6w) selected for the phase III studies are expected to be efficacious and able to achieve near-complete target engagement in the vitreous humor.
| S-EPMC4625864 | biostudies-literature
Project description:PurposeTo correlate retinal function and visual sensitivity with retinal morphology revealed by ultrahigh-resolution imaging with adaptive optics-optical coherence tomography (AO-OCT), on patients with geographic atrophy.MethodsFive eyes from five subjects were tested (four with geographic atrophy [66.3 ± 6.4 years, mean ± 1 SD] and one normal [61 years]). Photopic and scotopic multifocal electroretinograms (mfERGs) were recorded. Visual fields were assessed with microperimetry (mP) combined with a scanning laser ophthalmoscope for high-resolution confocal retinal fundus imaging. The eye tracker of the microperimeter identified the preferred retinal locus that was then used as a reference for precise targeting of areas for advanced retinal imaging. Images were obtained with purpose-built, in-house, ultrahigh resolution AO-OCT. Fundus autofluorescence (FAF) and color fundus (CF) photographs were also acquired.ResultsThe AO-OCT imaging provided detailed cross-sectional structural representation of the retina. Up to 12 retinal layers were identified in the normal subject while many severe retinal abnormalities (i.e., calcified drusen, drusenoid pigment epithelium detachment, outer retinal tubulation) were identified in the retinae of the GA patients. The functional tests showed preservation of sensitivities, although somewhat compromised, at the border of the GA.ConclusionsThe images provided here advance our knowledge of the morphology of retinal layers in GA patients. While there was a strong correlation between altered retinal structure and reduction in visual function, there were a number of examples in which the photoreceptor inner/outer segment (IS/OS) junctions lost reflectivity at the margins of GA, while visual function was still demonstrated. This was shown to be due to changes in photoreceptor orientation near the GA border.
| S-EPMC3694790 | biostudies-literature
Project description:PurposeThere is a lack of agreement regarding the types of lesions and clinical conditions that should be included in the term "geographic atrophy." Varied and conflicting views prevail throughout the literature and are currently used by retinal experts and other health care professionals.MethodsWe reviewed the nominal definition of the term "geographic atrophy" and conducted a search of the ophthalmologic literature focusing on preceding terminologies and the first citations of the term "geographic atrophy" secondary to age-related macular degeneration.ResultsAccording to the nominal definition, the term "geography" stands for a detailed description of the surface features of a specific region, indicating its relative position. However, it does not necessarily imply that the borders of the region must be sharply demarcated or related to any anatomical structures. The term "geographical areas of atrophy" was initially cited in the 1960s in the ophthalmologic literature in the context of uveitic eye disease and shortly thereafter also for the description of variants of "senile macular degeneration." However, no direct explanation could be found in the literature as to why the terms "geographical" and "geographic" were chosen. Presumably the terms were used as the atrophic regions resembled the map of a continent or well-defined country borders on thematic geographical maps. With the evolution of the terminology, the commonly used adjunct "of the retinal pigment epithelium" was frequently omitted and solely the term "geographic atrophy" prevailed for the nonexudative late-stage of age-related macular degeneration itself. Along with the quantification of atrophic areas, based on different imaging modalities and the use of both manual and semiautomated approaches, various and inconsistent definitions for the minimal lesion diameter or size of atrophic lesions have also emerged.ConclusionReconsideration of the application of the term "geographic atrophy" in the context of age-related macular degeneration seems to be prudent given ongoing advances in multimodal retinal imaging technology with identification of various phenotypic characteristics, and the observation of atrophy development in eyes under antiangiogenic therapy.
| S-EPMC5115977 | biostudies-literature
Project description:PurposeOur previous study demonstrated significantly more degranulating mast cells (MCs) in choroids from subjects with age-related macular degeneration compared to aged controls. This study examined the immunolocalization of tryptase, the most abundant MC secretory granule-derived serine protease, in aged control eyes and eyes with geographic atrophy (GA).MethodsPostmortem human eyes with and without GA were obtained from the National Disease Research Interchange. Tissue was fixed, cryopreserved, sectioned, and immunostained with a monoclonal antibody against tryptase. Sections were imaged on a Zeiss 710 Confocal Microscope.ResultsIn the posterior pole of all aged control eyes, tryptase was confined to choroidal MCs, which were located primarily in Sattler's layer. In eyes with GA, many MCs were located in the inner choroid near choriocapillaris and Bruch's membrane (BM). Tryptase was found not only in MCs but also diffusely around them in stroma, suggesting they had degranulated. In contrast with aged control eyes, eyes with GA also had strong tryptase staining in BM. Tryptase was observed within BM in regions of RPE atrophy, at the border of atrophy, and extending well into the nonatrophic region.ConclusionsOur results demonstrate that tryptase, released during choroidal MC degranulation, binds to BM in GA in advance of RPE atrophy. Tryptase activates MMPs that can degrade extracellular matrix (ECM) and basement membrane components found in BM. ECM modifications are likely to have a profound effect on the function and health of RPE and choroidal thinning in GA.
| S-EPMC5699534 | biostudies-literature
Project description:PurposeThe purpose of this study was to describe the presence of choroidal hyper-reflective foci (HRF) on optical coherence tomography (OCT) in patients with geographic atrophy (GA). The relationship between the presence and quantity of choroidal HRF and other clinical and imaging factors was also investigated.MethodsA total of 40 participants (40 eyes) with GA and age-related macular degeneration (AMD) were retrospectively analyzed. OCT images were reviewed for the presence, characteristics, and localization of choroidal HRF. The amount of choroidal HRF was quantified in different choroidal layers by two different (i.e. threshold reflectivity and manual counting) methodologies. The primary outcome was to describe and quantify choroidal HRF and correlate them with GA lesion size.ResultsStructural OCT images showed that all patients had multiple hyper-reflective deposits in different layers of the choroid. These hyper-reflective deposits in the choroid were located near Bruch's membrane or the edges of the blood vessels, particularly in the Sattler's layer, and none were observed inside the vessels. Choroidal HRF exhibited variable size and shape and varying effects on the posterior signal, including shadowing or hypertransmission. Mean ± SD number of choroidal HRF per B-scan was 21.5 ± 15.4 using the threshold reflectivity methodology and 25.1 ± 16.0 using the manual counting methodology. A significant correlation between the untransformed GA size and number of HRF was found, considering both quantitative strategies.ConclusionsHyper-reflective dots in the choroid of subjects with GA may be readily identified with structural OCT. These HRF might represent a natural component of the choroid that becomes more visible due to the absence of the retinal pigment epithelium.
| S-EPMC10629518 | biostudies-literature