The Pathophysiology of Geographic Atrophy Secondary to Age-Related Macular Degeneration and the Complement Pathway as a Therapeutic Target

Boyer, David S.; Schmidt‐Erfurth, Ursula; Campagne, Menno van Lookeren; Henry, Erin C.; Brittain, Christopher

doi:10.1097/iae.0000000000001392

Cited by 183 publications

(177 citation statements)

References 142 publications

(203 reference statements)

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“…Geographic atrophy (GA) is a progressive, advanced form of age-related macular degeneration (AMD), and is characterized by irreversible atrophy of the retinal pigment epithelium photoreceptors and choriocapillaris, 1,2 and is therefore associated with significant, irreversible loss of vision. 3 GA is estimated to affect 5 million people worldwide, 4 and to account for approximately one-quarter of cases of legal blindness in the United Kingdom, 1,5 and 20% of cases in North America. 2 GA has also been associated with more cases of legal blindness (severe sight loss/registered blind) in England and Wales than other forms of AMD.…”

Section: Introductionmentioning

confidence: 99%

<p>Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use</p>

Patel¹,

Ziemssen²,

Ng³

et al. 2020

OPTH

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Purpose: To gain comprehensive information on the burden of illness due to geographic atrophy (GA). Methods: This cross-sectional study with a retrospective chart review involved patients aged ≥70 years with physician-confirmed bilateral symptomatic GA due to age-related macular degeneration (GA group), as well as patients of similar age with no ophthalmic condition that in the opinion of the investigator affected visual function (non-GA group). Data relating to patients' current disease status and sociodemographics were self-reported on patient questionnaires at study entry and extracted from patient charts. Historical data on health care resource utilization (HCRU) were also collected via patient questionnaires and retrospective chart review (GA group only). Overall vision-related functioning and quality of life (QoL) were compared between the GA and non-GA groups using the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) composite and subscales, and change in vision over the past year was assessed using the Global Rating of Change Scale. Results: Vision-related functioning and QoL were poorer in patients with vs without GA (n=137 vs 52), as demonstrated by significantly lower NEI-VFQ-25 composite score (mean, 53.1 vs 84.5 points, respectively; P<0.001), as well as lower subscale scores for near activities, distance activities, dependency, driving, social functioning, mental health, role difficulties, color vision, and peripheral vision. Substantially more patients with GA than without GA reported worsening in vision over the past year (82% vs 25%, respectively; odds ratio, 13.55; P<0.001). In the GA group, associated mean annual costs for direct ophthalmological resource use per patient amounted to €1772 (mostly for tests/procedures), and for indirect ophthalmological resource use, €410 (mostly for general practitioner visits). Conclusion: Patients with GA experience a poorer level of vision-related function and QoL than their peers, especially in relation to driving. GA is also associated with notable HCRU/ associated costs, mostly direct costs attributed to diagnostic tests/procedures.

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Section: Introductionmentioning

confidence: 99%

<p>Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use</p>

Patel¹,

Ziemssen²,

Ng³

et al. 2020

OPTH

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“…However, RPE pathology does not get triggered in a single location to spread uniformly from there; but rather RPE damage occurs in multiple locations within the central part of the eye, that finally coalesce to form a region of atrophy (geographic atrophy, GA) [13]. This observation suggests that pathology occurs in susceptible regions, while healthy regions are protected; and that damage may occur randomly, in a stochastic fashion, or once triggered in a susceptible area, might spread via yet to be discovered means to other receptive areas.…”

Section: Introductionmentioning

confidence: 99%

Extracellular vesicle-mediated long-range communication in stressed retinal pigment epithelial cell monolayers

Shah

Ishii

Brandon

et al. 2018

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Retinal pigment epithelium (RPE) alterations in age-related macular degeneration occur in patches, potentially involving long-distance communication between damaged and healthy areas. Communication along the epithelium might be mediated by extracellular vesicles (EVs). To test this hypothesis, EVs were collected from supernatants of polarized ARPE-19 and primary porcine RPE monolayers for functional and biochemical assays. EVs from oxidatively stressed donor cells reduced barrier function in recipient RPE monolayers when compared to control EVs. The effect on barrier function was dependent on EV uptake, which occurred rapidly with EVs from oxidatively stressed donor cells. Mass spectrometry-based proteomic analysis of EVs identified HDAC6, which is known to reduce tight junction stability. Activity assays confirmed the presence of HDAC6 in EVs, and EV transfer assays using HDAC6 inhibitors confirmed its effect in monolayers. These findings demonstrate that EVs can communicate stress messages to healthy RPE cells, potentially contributing to RPE dysfunction.

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“…For example, lampalizumab, an antibody directed against complement factor D, could be used for its potential therapeutic effect, but it was disproved by Chroma and Spectry during phase 3 clinical trials [22][23][24]. At this moment, APL-2, that binds the C3 protein blocking all three pathways of complement activation, may be the most promising molecule [29][30][31][32]. The clinical trials Oaks and Derby, enrolling 600 patients each and ongoing on 58 different locations, will be completed in 2022 [29][30][31].…”

Section: Discussionmentioning

confidence: 99%

“…A phase 1 study (NCT01835015) has ended in 2016; it has evaluated the safety, tolerability, and serum pharmacokinetics of CLG561 in subjects with AMD. A phase 2 study (NCT02515942) started on 2015 enrolling 114 participants, to evaluate the safety and efficacy of 12 (every 28 days) IVTs of CLG561 as a monotherapy and in combination with LFG316 as compared to sham in subjects with GA [31,32]. The study was completed, but the reporting date is on August 2020.…”

Section: Clg561mentioning

confidence: 99%

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Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules

Nebbioso¹,

Lambìase²,

Cerini³

et al. 2019

Preprint

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The present review focuses on recent clinical trials that analyze the efficacy of intravitreal therapeutic agents for the treatment of dry age-related macular degeneration (AMD), such as neuroprotective drugs, and complement inhibitors, also called immunomodulatory or anti-inflammatory. A systematic literature search was performed to identify randomized controlled trials published prior to January 2019. Patients affected by dry AMD treated with intravitreal therapeutic agents were included. The changes in the correct visual acuity and the reduction in geographic atrophy progression were evaluated. Several new drugs have shown some promising results, including those targeting the complement cascade and agents called neuroprotective. The action potential of the two groups of drugs is to block the complement cascade model for immunomodulating agents, and prevent the degeneration and apoptosis of ganglion cells for the neuroprotectors, respectively. To the best of knowledge, and after extensive studies on the matter, there are still many investigations to be carried out on dry AMD in collaboration between researchers. They will have to identify truly effective molecules, understand the practical potential of pluripotent stem cells, and refine gene therapies. Only in-depth clinical trials will be able to allow the most appropriate and personalized treatments for each dry AMD patient.

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The Pathophysiology of Geographic Atrophy Secondary to Age-Related Macular Degeneration and the Complement Pathway as a Therapeutic Target

Cited by 183 publications

References 142 publications

<p>Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use</p>

<p>Burden of Illness in Geographic Atrophy: A Study of Vision-Related Quality of Life and Health Care Resource Use</p>

Extracellular vesicle-mediated long-range communication in stressed retinal pigment epithelial cell monolayers

Therapeutic Approaches with Intravitreal Injections in Geographic Atrophy Secondary to Age-Related Macular Degeneration: Current Drugs and Potential Molecules

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