Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

Guimarães, Thales Antonio Cabral de; Georgiou, Michalis; Bainbridge, James; Michaelides, Michel

doi:10.1136/bjophthalmol-2020-316195

Cited by 65 publications

(46 citation statements)

References 78 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This could, on the one hand, limit the therapeutic effect on neovessels, but on the other be beneficial to maintain a basal Müller cell homeostasis function that is key for normal neuronal function, which we demonstrated here. In the case of gene therapeutic approaches, e.g., expressing the therapeutic antibody via adeno-associated virus (AAV)-based vectors and as currently tested in clinical trials targeting the VEGF pathway ([ 71 , 72 ]; reviewed in [ 73 ]), we would speculate that unwarranted side effects on Müller cell homeostatic functions would be more pronounced. This hypothesis is supported be findings from VEGF knockout mice, demonstrating that total absence thereof leads to neurodegeneration [ 10 ].…”

Section: Discussionmentioning

confidence: 99%

PDGF Receptor Alpha Signaling Is Key for Müller Cell Homeostasis Functions

Díaz‐Lezama

Wolf

Koch

et al. 2021

IJMS

View full text Add to dashboard Cite

Müller cells, the major retinal macroglia, are key to maintaining vascular integrity as well as retinal fluid and ion homeostasis. Although platelet derived growth factor (PDGF) receptor expression in Müller glia has been reported earlier, their actual role for Müller cell function and intimate interaction with cells of the retinal neurovascular unit remains unclear. To close this gap of knowledge, Müller cell-specific PDGF receptor alpha (PDGFRα) knockout (KO) mice were generated, characterized, and subjected to a model of choroidal neovascularization (CNV). PDGFRα-deficient Müller cells could not counterbalance hypoosmotic stress as efficiently as their wildtype counterparts. In wildtypes, the PDGFRα ligand PDGF-BB prevented Müller cell swelling induced by the administration of barium ions. This effect could be blocked by the PDGFR family inhibitor AC710. PDGF-BB could not restore the capability of an efficient volume regulation in PDGFRα KO Müller cells. Additionally, PDGFRα KO mice displayed reduced rod and cone-driven light responses. Altogether, these findings suggest that Müller glial PDGFRα is central for retinal functions under physiological conditions. In contrast, Müller cell-specific PDGFRα KO resulted in less vascular leakage and smaller lesion areas in the CNV model. Of note, the effect size was comparable to pharmacological blockade of PDGF signaling alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy—a treatment regimen currently being tested in clinical trials. These data imply that targeting PDGF to treat retinal neovascular diseases may have short-term beneficial effects, but may elicit unwarranted side effects given the putative negative effects on Müller cell homeostatic functions potentially interfering with a long-term positive outcome.

show abstract

Section: Discussionmentioning

confidence: 99%

PDGF Receptor Alpha Signaling Is Key for Müller Cell Homeostasis Functions

Díaz‐Lezama

Wolf

Koch

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…1 2 Its progressive and irreversible nature translates to a significant societal cost burden and increased health resource utilisation. [3][4][5] Moreover, ageing is the main risk factor to develop AMD, hence, as life expectancy increases, this burden will ultimately become greater in the foreseeable future.…”

Section: Introductionmentioning

confidence: 99%

Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions

et al. 2021

Self Cite

View full text Add to dashboard Cite

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the developed world. The identification of the central role of vascular endothelial growth factor (VEGF) in the pathogenesis of neovascular AMD and the introduction of anti-VEGF agents as gold-standard treatment, have drastically changed its prognosis—something yet to be seen in dry AMD. Several therapeutic avenues with a wide variability of targets are currently being investigated in dry AMD. The approaches being investigated to reduce the rate of disease progression include, (1) drugs with antioxidative properties, (2) inhibitors of the complement cascade, (3) neuroprotective agents, (4) visual cycle inhibitors, (5) gene therapy and (6) cell-based therapies. A number of early phase clinical trials have provided promising results, with many more ongoing and anticipated in the near future. In this review, we aim to provide an update of the interventional trials to date and future prospects for the treatment of dry AMD.

show abstract

“…dry or non-neovascular AMD, and wet or neovascular AMD [nAMD]). 5 The latter form is characterized by invasion of new vessels from the choroid (CNV) causing irreversible damage to the retinal tissue. 6 Vascular endothelial growth factor (VEGF) is an important driver for CNV development 7 and the introduction of anti-VEGF antibodies for intravitreal injection has improved the treatment of nAMD significantly.…”

Section: Introductionmentioning

confidence: 99%

Subretinal Saline Protects the Neuroretina From Thermic Damage During Laser Induction of Experimental Choroidal Neovascularization in Pigs

Hansen

Askou

Cour

et al. 2021

Trans. Vis. Sci. Tech.

View full text Add to dashboard Cite

Purpose The purpose of this study was to develop a porcine model for photocoagulation induced choroidal neovascularization (CNV) with high success rate and minimal thermic damage to the neuroretina. Methods Experimental CNV was induced by laser photocoagulation in both eyes of 16 domestic pigs. In the left eyes, photocoagulation was preceded by subretinal injection of saline to protect the neuroretina from thermic damage, whereas the right eyes were treated with photocoagulation only. The development of the CNV after 3, 7, 14, 28, and 42 days was evaluated by optical coherence tomography (OCT) scanning, fluorescein angiography, and OCT angiography, and by histology after enucleation. Results From day 7 after the photocoagulation, OCT showed subretinal density in all lesions of 14 alive animals, and either fluorescein or OCT angiography confirmed CNV formation in 11 of 14 of the eyes that had received photocoagulation alone and those in which photocoagulation had been preceded by subretinal injection of saline. In all cases pretreated with subretinal saline, the neuroretina was protected from immediate thermic damage. The formation of CNVs were confirmed by histology. For both groups, the largest lesions were observed within 14 days after photocoagulation. Conclusions Injection of subretinal saline can protect the retina from thermic damage induced by retinal photocoagulation without reducing the success rate in producing experimental CNV. The effect of interventional studies aimed at reducing photocoagulation induced experimental CNV in pigs can be evaluated within 2 weeks after photocoagulation. Translational Relevance This model provides a fundament to develop and evaluate novel treatment methods for neovascular retinal diseases.

show abstract

Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions

Cited by 65 publications

References 78 publications

PDGF Receptor Alpha Signaling Is Key for Müller Cell Homeostasis Functions

PDGF Receptor Alpha Signaling Is Key for Müller Cell Homeostasis Functions

Treatments for dry age-related macular degeneration: therapeutic avenues, clinical trials and future directions

Subretinal Saline Protects the Neuroretina From Thermic Damage During Laser Induction of Experimental Choroidal Neovascularization in Pigs

Contact Info

Product

Resources

About