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Cited by 370Retinal Diseases and TreatmentsAngiogenesis and VEGF in CancerOcular Diseases and Behçet’s Syndrome

Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities

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Mettu, Priyatham S., Allingham, Michael J., Cousins, Scott W.·2021·Progress in Retinal and Eye Research
DOI 10.1016/j.preteyeres.2020.100906PMC PMC10368393
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Abstract

Intravitreal anti-vascular endothelial growth factor (VEGF) drugs have revolutionized the treatment of neovascular age-related macular degeneration (NVAMD). However, many patients suffer from incomplete response to anti-VEGF therapy (IRT), which is defined as (1) persistent (plasma) fluid exudation; (2) unresolved or new hemorrhage; (3) progressive lesion fibrosis; and/or (4) suboptimal vision recovery. The first three of these collectively comprise the problem of persistent disease activity (PDA) in spite of anti-VEGF therapy. Meanwhile, the problem of suboptimal vision recovery (SVR) is defined as a failure to achieve excellent functional visual acuity of 20/40 or better in spite of sufficient anti-VEGF treatment. Thus, incomplete response to anti-VEGF therapy, and specifically PDA and SVR, represent significant clinical unmet needs. In this review, we will explore PDA and SVR in NVAMD, characterizing the clinical manifestations and exploring the pathobiology of each. We will demonstrate that PDA occurs most frequently in NVAMD patients who develop high-flow CNV lesions with arteriolarization, in contrast to patients with capillary CNV who are highly responsive to anti-VEGF therapy. We will review investigations of experimental CNV and demonstrate that both types of CNV can be modeled in mice. We will present and consider a provocative hypothesis: formation of arteriolar CNV occurs via a distinct pathobiology, termed neovascular remodeling (NVR), wherein blood-derived macrophages infiltrate the incipient CNV lesion, recruit bone marrow-derived mesenchymal precursor cells (MPCs) from the circulation, and activate MPCs to become vascular smooth muscle cells (VSMCs) and myofibroblasts, driving the development of high-flow CNV with arteriolarization and perivascular fibrosis. In considering SVR, we will discuss the concept that limited or poor vision in spite of anti-VEGF may not be caused simply by photoreceptor degeneration but instead may be associated with photoreceptor synaptic dysfunction in the neurosensory retina overlying CNV, triggered by infiltrating blood-derived macrophages and mediated by Müller cell activation Finally, for each of PDA and SVR, we will discuss current approaches to disease management and treatment and consider novel avenues for potential future therapies.

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  • Sustained VEGF inhibition has been associated with adverse effects, including increased risk of ocular complications such as endophthalmitis, intraocular inflammation, and atrophic changes.

    “Moreover, sustained VEGF inhibition has been associated with adverse effects, including increased risk of ocular complications such as endophthalmitis, intraocular inflammation, and atrophic changes 12”

    From rAAV-mediated Multi-miRNA Delivery Targeting MAPK Pathway Suppresses Laser-induced Choroidal Neovascularization in Mice (2026) · cites this paper as [12]

    The Introduction discusses incomplete response despite sustained anti-VEGF treatment, and the Clinical manifestations section discusses persistent disease activity; neither attributes endophthalmitis, intraocular inflammation, or atrophic changes to VEGF inhibition. Searches for those complications and for atrophy found no passage in our copy making the claimed association. (LLM, conf=0.73)

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200 of 352 shown

Authors
Mettu, P. S., Allingham, M. J., & Cousins, S. W.
Affiliations
Duke University (US)
Corresponding author
Mettu, Priyatham S.
ORCID
Cousins, Scott W.
Venue
Progress in Retinal and Eye Research
Publisher
Elsevier BV
Published
2021-05
Volume
82
Pages
100906
ISSN
1350-9462 (ISSN-L)
DOI
10.1016/j.preteyeres.2020.100906
PMC
PMC10368393
OpenAlex
W3089551374
Cited by
370
References
422
Citations by year
2026: 63 · 2025: 92 · 2024: 85 · 2023: 62 · 2022: 54 · 2021: 13 · 2020: 1
FWCI
5.54
Type
journal article
Language
en
Open access
Licence
Locations
  • Progress in Retinal and Eye Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Research to Prevent Blindness
  • Bausch and Lomb
  • National Institutes of Health
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
Keywords
neovascular age-related macular degeneration, anti-VEGF therapy, choroidal neovascularization, macrophage infiltration, mesenchymal precursor cells, vascular smooth muscle cells, myofibroblasts, perivascular fibrosis, Müller cell activation
MeSH terms
Animals, Humans, Visual Acuity, Choroidal Neovascularization, Angiogenesis Inhibitors, Vascular Endothelial Growth Factor A, Mice, Wet Macular Degeneration, Intravitreal Injections

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