scholarly journals A novel ferrochelatase inhibitor as a therapy for ocular neovascularization

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Sydney Waller ◽  
Sheik Pran Babu Sardar Pasha ◽  
Nathan Lambert-Cheatham ◽  
Timothy W. Corson
Keyword(s):  
Optical Coherence Tomography ◽  
Choroidal Neovascularization ◽  
High Throughput Screening ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Optical Coherence ◽  
Ocular Neovascularization ◽  
Age Related

Background and Hypothesis: Ocular neovascularization, characterized by the abnormal growth of new blood vessels, underlies blindness-inducing diseases such as wet age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). This neovascularization can be either choroidal (in the case of wet AMD) or retinal (in the case of PDR). Inhibition of vascular endothelial growth factor is the target of current FDA approved therapies, however the need for intravitreal injections poses a drawback to such treatments. Furthermore, many patients are non-responders or refractory. Given this, the discovery of novel therapeutic targets is warranted. Ferrochelatase (FECH) is an enzyme involved in heme synthesis. The Corson lab has previously shown FECH to be necessary for angiogenesis both in vitro and in vivo. The Corson lab has been successful in developing novel compounds that inhibit FECH in vitro, based on high-throughput screening hits. The objective of this project was to test one such novel FECH inhibitor in a choroidal neovascularization mouse model. Experimental Design: FECH inhibition was investigated in the laser-induced choroidal neovascularization model. This model involved creating a laser-induced lesion into the retinal pigment epithelium/choroid of mice aged 6-8 weeks; this promotes neovascularization. The FECH inhibitor compound was delivered once intravitreally at the time of the laser. Neovascularization was analyzed in vivo using optical coherence tomography and fluorescein angiography one and two weeks after laser, then quantified ex vivo by isolectin staining. Results: There was a trend toward decreased ocular neovascularization with the administration of a FECH inhibitor, as measured by optical coherence tomography seven days after laser treatment. However, further analyses are ongoing to validate this finding. Conclusion and Potential Impact: The administration of a FECH inhibitor compound intravitreally may result in a decrease in CNV. This may be useful as it could lead to FECH serving as a target for future therapies.

scholarly journals Optimal Inhibition of Choroidal Neovascularization by scAAV2 with VMD2 Promoter-driven Active Rap1a in the RPE

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Haibo Wang ◽  
Eric Kunz ◽  
Gregory J. Stoddard ◽  
William W. Hauswirth ◽  
M. Elizabeth Hartnett
Keyword(s):  
Choroidal Neovascularization ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Term Treatment ◽  
Age Related Macular Degeneration ◽  
Promising Tool ◽  
Age Related ◽  
Long Term Treatment

Abstract Age-related macular degeneration (AMD) is a multifactorial chronic disease that requires long term treatment. Gene therapy is being considered as a promising tool to treat AMD. We found that increased activation of Rap1a in the retinal pigment epithelium (RPE) reduces oxidative signaling to maintain barrier integrity of the RPE and resist neural sensory retinal angiogenesis from choroidal endothelial cell invasion. To optimally deliver constitutively active Rap1a (CARap1a) into the RPE of wild type mice, self-complementary AAV2 (scAAV2) vectors driven by two different promoters, RPE65 or VMD2, were generated and tested for optimal active Rap1a expression and inhibition of choroidal neovascularization (CNV) induced by laser injury. scAAV2-VMD2, but not scAAV2-RPE65, specifically and efficiently transduced the RPE to increase active Rap1a protein in the RPE. Mice with increased Rap1a from the scAAV2-VMD2-CARap1a had a significant reduction in CNV compared to controls. Increased active Rap1a in the RPE in vivo or in vitro inhibited inflammatory and angiogenic signaling determined by decreased activation of NF-κB and expression of VEGF without causing increased cell death or autophagy measured by increased LCA3/B. Our study provides a potential future strategy to deliver active Rap1a to the RPE in order to protect against both atrophic and neovascular AMD.

scholarly journals Crosstalk between RPE cells and choroidal endothelial cells via the ANXA1/FPR2/SHP2/NLRP3 inflammasome/pyroptosis axis promotes choroidal neovascularization

2021 ◽  
Author(s):  
Manhui Zhu ◽  
Ying Wang ◽  
Linling Zhu ◽  
Shu Du ◽  
Zhenzhen Wang ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Choroidal Neovascularization ◽  
Nlrp3 Inflammasome ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Inflammasome Activation ◽  
Rpe Cells ◽  
Age Related

Abstract One type of age-related macular degeneration (AMD), neovascular (nAMD), characterized by choroidal neovascularization (CNV), accounts for the majority of the severe central vision impairment associated with AMD. Endothelial cells (ECs) in direct contact with retinal pigment epithelial (RPE) cells are more prone to the pathological angiogenesis involved in CNV. Herein, we investigated the effect of crosstalk between RPE cells and choroidal endothelial cells (CECs) via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis on the development of choroidal neovascularization (CNV) in vitro and in vivo. ANXA1 expression and secretion from ARPE-19 cells were upregulated by hypoxia. FPR2 expression, especially on the plasma membrane, in HCECs was upregulated under hypoxic conditions. ANXA1 secreted from ARPE-19 cells inhibited NLRP3 inflammasome activation and NLRP3 inflammasome-mediated pyroptosis in HCECs by activating the FPR2/SHP2 axis. Moreover, ANXA1 secreted by ARPE-19 cells promoted behaviors of HCECs, including proliferation, migration and tube formation, by activating the FPR2/SHP2 axis and inhibiting NLRP3 inflammasome-mediated pyroptosis. Inhibiting the upregulated ANXA1/FPR2/SHP2/NLRP3 inflammasome/pyroptosis axis decreased the volume of CNV. Our data suggest that the crosstalk between RPE cells and CECs via the ANXA1/FPR2/NLRP3 inflammasome/pyroptosis axis promotes CNV. This finding could identify a potential target for the prevention and treatment of CNV.

scholarly journals Complement C5 is not critical for the formation of sub-RPE deposits in Efemp1 mutant mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Donita L. Garland ◽  
Eric A. Pierce ◽  
Rosario Fernandez-Godino
Keyword(s):  
Macular Degeneration ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Deposit Formation ◽  
Genetic Ablation ◽  
Age Related ◽  
Complement Dysregulation

AbstractThe complement system plays a role in the formation of sub-retinal pigment epithelial (RPE) deposits in early stages of age-related macular degeneration (AMD). But the specific mechanisms that connect complement activation and deposit formation in AMD patients are unknown, which limits the development of efficient therapies to reduce or stop disease progression. We have previously demonstrated that C3 blockage prevents the formation of sub-RPE deposits in a mouse model of EFEMP1-associated macular degeneration. In this study, we have used double mutant Efemp1R345W/R345W:C5-/- mice to investigate the role of C5 in the formation of sub-RPE deposits in vivo and in vitro. The data revealed that the genetic ablation of C5 does not eliminate the formation of sub-RPE deposits. Contrarily, the absence of C5 in RPE cultures promotes complement dysregulation that results in increased activation of C3, which likely contributes to deposit formation even in the absence of EFEMP1-R345W mutant protein. The results also suggest that genetic ablation of C5 alters the extracellular matrix turnover through an effect on matrix metalloproteinases in RPE cell cultures. These results confirm that C3 rather than C5 could be an effective therapeutic target to treat early AMD.

Pachychoroid Neovasculopathy; Findings, Diagnosis, and Treatment

2020 ◽  
pp. 112-117
Keyword(s):  
Optical Coherence Tomography ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Current Treatment ◽  
Age Related Macular Degeneration ◽  
Optical Coherence ◽  
Age Related ◽  
Pachychoroid Neovasculopathy ◽  
Sign Type

Pachychoroid neovasculopathy (PNV) is a novel clinical entity with typical pachychoroid features accompanied by type 1 choroidal neovascularization (CNV). Typical optical coherence tomography finding of the disease is flat irregular pigment epithelial detachments (double layer sign). Type 1 CNV between retinal pigment epithelium and Bruch membrane is seen as a tangled network on optical coherence tomography angiography. Differential diagnosis of PNV from neovascular age-related macular degeneration is especially important because of the different epidemiological, genetic, and therapeutic features of these diseases. Current treatment approaches include intravitreal anti-vascular endothelial growth factor injections and photodynamic therapy.

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