Treatment Of Choroidal Neovascularization Research Articles

Transcriptomic analysis of choroidal neovascularization reveals dysregulation of immune and fibrosis pathways that are attenuated by a novel anti-fibrotic treatment

Neovascular AMD (nAMD) leads to vision loss and is a leading cause of visual impairment in the industrialised world. Current treatments that target blood vessel growth have not been able to treat subretinal fibrosis and nAMD patients continue to lose vision. The molecular mechanisms involved in the development of fibrotic lesions in nAMD are not well understood. The aim of this study was to further understand subretinal fibrosis in the laser photocoagulation model of choroidal neovascularization (CNV) by studying the whole transcriptome of the RPE/choroid following CNV and the application of an anti-fibrotic following CNV. Seven days after laser induced CNV, RPE and choroid tissue was separated and underwent RNAseq. Differential expression analysis and pathway analysis revealed an over representation of immune signalling and fibrotic associated pathways in CNV compared to control RPE/choroid tissue. Comparisons between the mouse CNV model to human CNV revealed an overlap in upregulated expression for immune genes (Ccl2, Ccl8 and Cxcl9) and extracellular matrix remodeling genes (Comp, Lrcc15, Fndc1 and Thbs2). Comparisons between the CNV model and other fibrosis models showed an overlap of over 60% of genes upregulated in either lung or kidney mouse models of fibrosis. Treatment of CNV using a novel cinnamoyl anthranilate anti-fibrotic (OCX063) in the laser induced CNV model was selected as this class of drugs have previously been shown to target fibrosis. CNV lesion leakage and fibrosis was found to be reduced using OCX063 and gene expression of genes within the TGF-beta signalling pathway. Our findings show the presence of fibrosis gene expression pathways present in the laser induced CNV mouse model and that anti-fibrotic treatments offer the potential to reduce subretinal fibrosis in AMD.

Targeted Long-Term Noninvasive Treatment of Choroidal Neovascularization by Biodegradable Nanoparticles

Targeted Long-Term Noninvasive Treatment of Choroidal Neovascularization by Biodegradable Nanoparticles

Genetic Polymorphisms Affecting Ranibizumab Response in High Myopia Patients.

High myopia is an ophthalmic pathology that affects half of the young adults in the United States and Europe and it is predicted that a third of the world’s population could be nearsighted at the end of this decade. It is characterized by at least 6 diopters or axial length > 26 mm and, choroidal neovascularization (CNV) in 5 to 11% of cases. Ranibizumab is a recombinant humanized monoclonal antibody fragment. It is an anti-vascular endothelial growth factor (anti-VEGF) drug used in the treatment of CNV. Many genetic polymorphisms have been associated with interindividual differences in the response to ranibizumab, but these associations were not yet assessed among patients with high myopia and CNV. We performed a retrospective study assessing the association of genetic polymorphisms with response to ranibizumab in patients with CNV secondary to high myopia (mCNV). We included genetic polymorphisms previously associated with the response to drugs used in CNV patients (bevacizumab, ranibizumab, aflibercept, and photodynamic therapy (PDT)). We also included genetic variants in the VEGFA gene. Based on our results, ARMS2 (rs10490924) and CFH (rs1061170) are associated with response to ranibizumab in high myopia patients; and, included VEGFA genetic polymorphisms are not associated with ranibizumab response in our population but might be related to a higher risk of CNV.

Efficacy of Conbercept in the Treatment of Choroidal Neovascularization Secondary to Pathologic Myopia.

Purpose: To observe the clinical efficacy of conbercept in the treatment of choroidal neovascularization (CNV) secondary to pathologic myopia.Methods: We used retrospective analysis of the clinical data of 20 patients (24 eyes) with pathologic myopia choroidal neovascularization (PM-CNV). All patients were treated with intravitreal injection of conbercept 0.5 mg (0.05 ml), a vascular endothelial growth factor (VEGF) receptor fusion protein, and all patients completed at least 6 months of follow-up. Fundus, best corrected visual acuity (BCVA), fundus fluorescein angiography (FFA), optical coherence tomography (OCT), multifocal electroretinogram (mfERG) were assessed before and after treatment. Primary outcome was the functional change in amplitude by mfERG and secondary outcome was the structural change in central macular thickness (CRT) by OCT. The CNV area, leakage of CNV lesions, ocular and systemic adverse events were observed before and after treatment.Results: The BCVA were 64.33 ± 10.83 letters, 65.42 ± 11.24 letters, 67.67 ± 7.07 letters after treatment 1, 3, 6 month, respectively, which showed improvement compared with the baseline (P < 0.05). The CRT decreased significantly from 308.50 ± 45.48 μm to 219.63 ± 30.27 μm, 221.33 ± 40.65 μm, 220.96 ± 33.09 μm after treatment 1, 3, 6 month, respectively (P < 0.05). The P1 response of mfERG amplitude improved from 40.71 ± 9.69 nv/deg2 to 50.67 ± 9.48 nv/deg2, 54.92 ± 8.45 nv/deg2, 55.67 ± 6.74 nv/deg2 after treatment 1, 3, 6 month, respectively (P < 0.05). After 6 months of treatment, the leakage of CNV lesions disappeared in 20 (83.3%) eyes, and the leakage area of CNV lesions was significantly reduced in 4 (16.7%) eyes.Conclusion: The intravitreal injection of conbercept significantly reduced CRT and the CNV area, inhibited the leakage of CNV, improved the BCVA, increased the response of mfERG amplitude, and restored the retinal function. The intravitreal injection of conbercept can change the morphology and function of the macular in PM-CNV, which is safe and effective for the treatment of PM-CNV.

Crosstalk Between RPE Cells and Choroidal Endothelial Cells via the ANXA1/FPR2/SHP2/NLRP3 Inflammasome/Pyroptosis Axis Promotes Choroidal Neovascularization.

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.

RGD-modified multifunctional nanoparticles encapsulating salvianolic acid A for targeted treatment of choroidal neovascularization

BackgroundThe development of alternative anti-angiogenesis therapy for choroidal neovascularization (CNV) remains a great challenge. Nanoparticle systems have emerged as a new form of drug delivery in ocular diseases. Here, we report the construction and characterization of arginine-glycine-aspartic acid (RGD)-conjugated polyethyleneimine (PEI) as a vehicle to load antioxidant salvianolic acid A (SAA) for targeted anti-angiogenesis therapy of CNV. In this study, PEI was consecutively modified with polyethylene glycol (PEG) conjugated RGD segments, 3-(4′-hydroxyphenyl) propionic acid-Osu (HPAO), and fluorescein isothiocyanate (FI), followed by acetylation of the remaining PEI surface amines to generate the multifunctional PEI vehicle PEI.NHAc-FI-HPAO-(PEG-RGD) (for short, RGD-PEI). The formed RGD-PEI was utilized as an effective vehicle platform to load SAA.ResultsWe showed that RGD-PEI/SAA complexes displayed desirable water dispersibility, low cytotoxicity, and sustainable release of SAA under different pH conditions. It could be specifically taken up by retinal pigment epithelium (RPE) cells which highly expressed ɑvβ5 integrin receptors in vitro and selectively accumulated in CNV lesions in vivo. Moreover, the complexes displayed specific therapeutic efficacy in a mouse model of laser induced CNV, and the slow elimination of the complexes in the vitreous cavity was verified by SPECT imaging after 131I radiolabeling. The histological examinations further confirmed the biocompatibility of RGD-PEI/SAA.ConclusionsThe results suggest that the designed RGD-PEI/SAA complexes may be a potential alternative anti-angiogenesis therapy for posterior ocular neovascular diseases.Graphic abstract

Intravitreal Conbercept for Idiopathic Choroidal Neovascularization in Nursing Women.

Purpose: To report the clinical course and vascular endothelial growth factor (VEGF) levels in breast milk among three nursing women diagnosed with idiopathic choroidal neovascularization (CNV) before and after intravitreal injection of conbercept. Methods: This was an observational case series. The main outcomes and measures included best-corrected visual acuity (BCVA), anatomical features using optical coherence tomography, and breast milk concentrations of VEGF before and after the intravitreal injection of conbercept. Results: BCVA was increased, and no ocular or systemic safety problems were observed in any of the three patients during the follow-up period. An enzyme-linked immunosorbent assay was used to measure VEGF concentrations in the breast milk samples. Samples were collected 1 day before and 1, 7, and 30 days after the first intravitreal injection of conbercept. After conbercept injection, VEGF levels in breast milk were slightly decreased and did not change significantly in the following week; levels recovered fully by 30 days post-treatment. Conclusions: Intravitreal injection of conbercept shows favorable effectiveness and safety in the treatment of idiopathic CNV in nursing women and does not result in a significant reduction in VEGF in human breast milk.

Using optical coherence tomography angiography to guide myopic choroidal neovascularization treatment: a 3-year follow-up study.

To report the long-term changes of the size of myopic choroidal neovascularization (mCNV) using optical coherence tomography angiography (OCTA). This was a retrospective, observational case study of eleven eyes in eleven patients with mCNV followed with OCTA for a minimum of 3years. The flow area of mCNV on OCTA, the size of chorioretinal atrophy (CRA) and central choroidal thickness were analyzed. The relationship between the changes of mCNV size and recurrences treated with anti-vascular endothelial growth factor (VEGF) agents was also assessed. Three eyes out of eleven eyes showed enlargement of the mCNV over 3years. In two of the three eyes, the mCNV recurrences had not been treated immediately (the examination intervals were 4months and 5months, respectively), and we found obvious enlargement of the mCNV. In three eyes, the mCNV size decreased in 1year and was stable thereafter without recurrences. In five eyes, mCNV size did not show remarkable changes for 3years. In three of the five eyes, no recurrences were detected and two of the five eyes underwent prompt treatments against recurrences. Regular examination and prompt treatments against recurrences are critical to prevent enlargement of mCNV.

Real-World Anti-Vascular Endothelial Growth Factor Therapy Outcomes in Myopic Choroidal Neovascularization.

AimEvaluation of real-world outcomes of intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy in the primary treatment of choroidal neovascularization (CNV) secondary to pathological myopia.Patients and MethodsA retrospective cohort analysis of treatment naive patients with myopic CNV who received treatment with either intravitreal ranibizumab or aflibercept over a 12-year period from September 2007 to May 2020 was performed. Baseline features, treatment factors and outcomes were compared between younger and older patients and final visual outcome was assessed for associated factors.ResultsThirty-seven eyes of 36 patients (24 females, 12 males) were included. Mean age was 58 years (range=26–89 years). Of these patients, 11/36 (31%) were ≤50 years of age and 25/36 (69%) were ≥51 years of age. Seventy-three percent (27/37) of eyes were phakic. One patient received bilateral treatment for myopic CNV. Median spherical equivalent was −8.50 diopters. Seventy percent (26/37) of eyes commenced primary treatment with ranibizumab, and 11/37 (30%) eyes commenced treatment with aflibercept. There were no significant differences between treatment factors and outcomes of younger and older patients. Median number of injections was 3 over a median follow-up period of 24.6 months. Mean CRT decreased by 126μm and median visual improvement was +6 letters. Analysis showed that younger age (p=0.022) and fewer injections (p=0.004) were associated with better visual outcomes.ConclusionMyopic CNV requires less frequent anti-VEGF intravitreal therapy over a shorter follow-up period than both neovascular age-related macular degeneration and diabetic macular edema. Increased frequency of administration of intravitreal anti-VEGF treatment did not improve vision. Younger age is associated with a better final visual outcome. These findings may help to advise patients about the prognosis of treatment and help guide treatment decisions.

Анализ эффективности применения ингибитора ангиогенеза при лечении хориоидальной неоваскуляризации у пациентов с хронической формой центральной серозной хориоретинопатии

Purpose. To evaluate efficacy of angiogenesis inhibitor ranibizumab (Lucentis, Novartis, Switzerland) in treatment of choroidal neovascularization (CNV) in patients with chronic central serous chorioretinopathy (CSCR). Material and methods. The object of study was 11 patients (8 men and 3 women, 11 eyes) aged from 41 to 50 years with CNV on the background of chronic CSCR. All monitored patients underwent 3 consecutive “loading” intravitreal Lucentis injections is either 0.5 mg in 0.05 mL once a month. Results. After 3 months, all studied patients had complete obliteration of CNV. At the same time, the central retinal thickness was 224.5±13.3 µm, which did not differ significantly from norm (p&lt;0.05). All 11 patients had stabilization of visual functions with average index of best corrected visual acuity of 0.9±0.13, exceeding the initial level by 0.15±0.04 (p&lt;0.05), an increase in light sensitivity of central retinal zone was noted up to 22.41±1.2 dB. Conclusion. The data obtained allow us to state that timely use of angiogenesis inhibitor Lucentis in treatment of CNV in patients with the chronic CSCR is pathogenetically justified, effective and safe. Given frequency of recurrence, further studies of anti-VEGF therapy in treatment of chronic CSCR are needed to determine the need for repeated injections of anti-VEGF drugs. Key words: central serous chorioretinopathy, choroidal neovascularization, Lucentis.

Targeted Noninvasive Treatment of Choroidal Neovascularization by Hybrid Cell-Membrane-Cloaked Biomimetic Nanoparticles.

Choroidal neovascularization (CNV) is the leading cause of vision loss in many blinding diseases, but current antiangiogenic therapies with invasively intravitreal injection suffer from poor patient compliance and a rate of devastating ocular complications. Here, we develop an alternative antiangiogenic agent based on hybrid cell-membrane-cloaked nanoparticles for noninvasively targeted treatment of CNV. The retinal endotheliocyte membrane coating provides as-fabricated nanoagents with homotypic targeting capability and binding ability to the vascular endothelial growth factor. The fusion of red blood cell membranes protects the hybrid membrane-coated nanoparticles from phagocytosis by macrophages. In a laser-induced wet age-related macular degeneration mouse model, a significantly enhanced accumulation is observed in CNV regions after intravenous delivery of the hybrid membrane-coated nanoparticles. Moreover, an excellent therapeutic efficacy is achieved in reducing the leakage and area of CNV. Overall, the biomimetic antiangiogenic nanoagents provide an effective approach for noninvasive treatment of CNV.

An antibody-like peptidic network for anti-angiogenesis

Different from chemical (small molecular inhibitor) and biological (monoclonal antibody) drugs, herein, based on angiogenesis-related neuropilin-1 (NRP-1), we develop a biomimetic superstructure drug, i.e. an antibody-like peptidic network (ALPN) to achieve the high-efficient treatment of choroidal neovascularization (CNV). The ALPN in nanoparticulated formulation (ALPN-NPS) can bind NRP-1 through targeting unit and form fibrous peptidic networks trapping NRP-1 on the surface of endothelial cells (ECs), leading to anti-angiogenesis. The ALPN shows high-efficacy against angiogenesis in CNV rat model ascribed to the superstructure-enhanced binding and blockage of NRP-1. The very low dose of ALPN (0.263 μg/Kg) exhibits similar anti-angiogenesis effect comparing with monoclonal antibody bevacizumab (23.5 μg/Kg), which shows potential advantages over traditional monoclonal antibodies.

Synthetic anti-angiogenic genomic therapeutics for treatment of neovascular age-related macular degeneration

In light of the intriguing potential of anti-angiogenic approach in suppressing choroidal neovascularization, we attempted to elaborate synthetic gene delivery systems encapsulating anti-angiogenic plasmid DNA as alternatives of clinical antibody-based therapeutics. Herein, block copolymer of cyclic Arg-Gly-Asp-poly(ethylene glycol)-poly(lysine-thiol) [RGD-PEG-PLys(thiol)] with multifunctional components was tailored in manufacture of core-shell DNA delivery nanoparticulates. Note that the polycationic PLys segments were electrostatically complexed with anionic plasmid DNA into nanoscaled core, and the tethered biocompatible PEG segments presented as the spatial shell (minimizing non-specific reactions in biological milieu). Furthermore, the aforementioned self-assembly was introduced with redox-responsive disulfide crosslinking due to the thiol coupling. Hence, reversible stabilities, namely stable in extracellular milieu but susceptible to disassemble for liberation of the DNA payloads in intracellular reducing microenvironment, were verified to facilitate transcellular gene transportation. In addition, RGD was installed onto the surface of the proposed self-assemblies with aim of targeted accumulation and internalization into angiogenic endothelial cells given that RGD receptors were specifically overexpressed on their cytomembrane surface. The proposed anti-angiogenic DNA therapeutics were validated to exert efficient expression of anti-angiogenic proteins in endothelial cells and elicit potent inhibition of ocular neovasculature post intravitreous administration. Hence, the present study approved the potential of gene therapy in treatment of choroidal neovascularization. In light of sustainable gene expression properties of DNA therapeutics, our proposed synthetic gene delivery system inspired prosperous potentials in long-term treatment of choroidal neovascularization, which should be emphasized to develop further towards clinical translations.

Emerging biological therapies for the treatment of age-related macular degeneration

ABSTRACT Introduction Age-related macular degeneration (AMD) is the leading cause of blindness in individuals over age 50 in developed countries. Current therapy for nonexudative AMD (neAMD) is aimed at modifying risk factors and vitamin supplementation to slow progression, while intravitreal anti-vascular endothelial factor (VEGF) injections are the mainstay for treatment of choroidal neovascularization in exudative AMD (eAMD). Areas covered Over the past decade, promising therapies have emerged that aim to improve the current standard of care for both diseases. Clinical trials for neAMD are investigating targets in the complement cascade, vitamin A metabolism, metformin, and tetracycline, whereas clinical trials for eAMD are aiming to decrease treatment burden through novel port delivery systems, increasing drug half-life, and targeting new sites of the VEGF cascade. Stem cell and gene therapy are also being evaluated for treatment of neAMD and eAMD. Expert opinion With an aging population, the need for effective, long term, low burden treatment options for AMD will be in increasingly high demand. Current investigations aim to address the shortcomings of current treatment options with breakthrough treatment approaches. Therapeutics in the pipeline hold promise for improving the treatment of AMD, and are on track for widespread use within the next decade.

Intravitreal conbercept for choroidal neovascularisation secondary to pathological myopia in a real\u2010world setting in China

BackgroundTo evaluate the 12-month efficacy and safety of intravitreal conbercept for myopic choroidal neovascularization (CNV).MethodsA retrospective, observational study. Thirty-four eyes of 34 pathologic myopic patients with CNV were treated with intravitreal conbercept (IVC) 0.5 mg with a follow up of 12 months. After the first injection, administration of conbercept followed a pro re nata (PRN) regimen. Outcomes included best corrected visual acuity (BCVA), central retinal thickness (CRT), CNV size, the total number of treatments, and adverse events.ResultsThe mean patient age was 55.88 ± 16.17 years, and the mean eye spherical equivalent was − 8.72 ± 3.75 D. The mean number of IVC over 12 months was 2.12 ± 0.69. Overall, best-corrected visual acuity(BCVA)improved from 0.86 ± 0.33 logMAR at baseline to 0.44 ± 0.32 logMAR at month 12 (p < 0.001), mean improvement of vision was 4.12 ± 2.69 lines. Mean central retinal thickness reduced from 285.9 ± 104.6 µm at baseline to 192.1 ± 97.5 µm at month 12 (p < 0.001). Mean CNV size decreased from 0.52 ± 0.38 mm2 at baseline to 0.31 ± 0.19 mm2 at 12 months (p < 0.05). All the 34 eyes had reduced or stable size of CNV. Thirty-two eyes (94.12 %) showed the absence of CNV leakage at the end of the study period. No severe systemic or ocular adverse events were observed.ConclusionsIntravitreal conbercept 0.5 mg was safe and effective for treatment of myopic CNV over 12 months in a real-world setting.

Activated Protein C (APC) and 3K3A-APC-Induced Regression of Choroidal Neovascularization (CNV) Is Accompanied by Vascular Endothelial Growth Factor (VEGF) Reduction.

The activated protein C (APC) ability to inhibit choroidal neovascularization (CNV) growth and leakage was recently shown in a murine model. A modified APC, 3K3A-APC, was designed to reduce anticoagulant activity while maintaining full cytoprotective properties, thus diminishing bleeding risk. We aimed to study the ability of 3K3A-APC to induce regression of CNV and evaluate vascular endothelial growth factor (VEGF) role in APC’s activities in the retina. CNV was induced by laser photocoagulation on C57BL/6J mice. APC and 3K3A-APC were injected intravitreally after verification of CNV presence. CNV volume and vascular penetration were evaluated on retinal pigmented epithelium (RPE)-choroid flatmount by fluorescein isothiocyanate (FITC)-dextran imaging. VEGF levels were measured using immunofluorescence anti-VEGF staining. We found that 3K3A-APC induced regression of pre-existing CNV. VEGF levels, measured in the CNV lesion sites, significantly decreased upon APC and 3K3A-APC treatment. Reduction in VEGF was sustained 14 days post a single APC injection. As 3K3A-APC retained APCs’ activities, we conclude that the anticoagulant properties of APC are not mandatory for APC activities in the retina and that VEGF reduction may contribute to the protective effects of APC and 3K3A-APC. Our results highlight the potential use of 3K3A-APC as a novel treatment for CNV and other ocular pathologies.

Intravitreal Bevacizumab for the Treatment of Choroidal Neovascularization after Eyeball Perforation during Retrobulbar Anesthesia.

Intravitreal Bevacizumab for the Treatment of Choroidal Neovascularization after Eyeball Perforation during Retrobulbar Anesthesia.

Reactivation of CNV after Discontinuation of Bevacizumab Treatment of Age-Related Macular Degeneration

Introduction: Treatment of exudative age-related macular degeneration (ARMD) has shifted to pro re nata and treat-extend-stop strategies. However, a rational discontinuation strategy is lacking. To develop such a strategy, it is important to determine choroidal neovascularization (CNV) recurrence rates after anti-VEGF treatment is discontinued. Here we report prospective data on persistent and recurrent CNV activity after discontinuation of bevacizumab treatment. Methods: This prospective, single-center clinical trial enrolled 191 patients with exudative ARMD. Patients were randomly assigned to receiving intravitreal bevacizumab injections every 4, 6, or 8 weeks for 1 year. CNV activity was determined in the 157 patients who completed the 1-year treatment regimen. Patients with inactive CNV were then followed for signs of CNV reactivation. Results: After 1 year of treatment, 66 (42%) of the 157 patients still had signs of persistent active CNV. Of the remaining 91 (58%) patients, 61 (67%) needed retreatment for active CNV within the first year after discontinuation of treatment (mean 4.28 ± 0.29 months). CNV was reactivated in 50 (80%) of the 61 patients within 6 months after their final treatment for CNV. Conclusion: Based on quiescent disease, anti-VEGF therapy was discontinued in 58% of the patients after they received bevacizu­mab injections every 4, 6, or 8 weeks for 1 year; 67% showed reactivated CNV within a year after discontinuation. The high reactivation rate of CNV shown in this study should help clinicians to develop rational discontinuation protocols. Trial Registration: This study is registered as NTR1174 at http://www.trialregister.nl.

Repurposing bortezomib for choroidal neovascularization treatment via antagonizing VEGF-A and PDGF-D mediated signaling

Neovascular age-related macular degeneration (neoAMD) is the leading cause of blindness in AMD and manifests as choroidal neovascularization (CNV). Anti-vascular endothelial growth factor (VEGF) therapies are the mainstay treatments but with limited efficacy and cause detrimental effects on the retina after long-term application. These disadvantages warrant alternative strategy. Herein, we examined the effect on CNV by intravitreal injection of bortezomib, a reversible proteasome inhibitor, and further dissected the mechanism. Krypton red Laser was used to create CNV model in mice. The angiogenesis volume was assessed in choroidal flat-mount with isolectin GS-IB4 labeling and the leakage was examined with fluorescein fundus angiography. Injection of Borsub inhibited angiogenesis in the CNV model which was dose-dependent; the injection significantly inhibited leakage as well. Furthermore, Borsub injection reduced the contents of VEGF-A, macrophage chemotactic factor 1 (MCP-1), and platelet-derived growth factor (PDGF)-D but not PDGF-B, examined by enzyme-linked immunosorbent assay, in choroid/retinal pigment epithelium (RPE) tissue. These injections also reduced phospho-VEGFR-2 and phospho-PDGFRβ in choroid/RPE tissue examined by immunoblotting. Moreover, Borsub inhibited the recruitment of mural cells or macrophages to laser-injured spots. Injection of Borsub indicated negative effect on scotopic and photopic responses recorded by electroretinogram. Altogether, intravitreal injection of Borsub significantly reduced CNV by antagonizing VEGF-A/Flk-1 and PDGF-D/PDGFRβ pathways without impacting electroretinography parameters. Thus, Borsub may offer an invaluable therapy for the prevention and treatment of neoAMD.

Clinical Course of Treated Choroidal Neovascularization in Eyes with Pre-existing Geographic Atrophy: Case Series and Reappraisal of the Literature

ABSTRACT Purpose: To report the clinical course of choroidal neovascularization (CNV) treated with anti-vascular endothelial growth factor (VEGF) treatment in eyes with pre-existing geographic atrophy (GA). Material and Methods: Multicenter retrospective series. Electronic medical records, clinical notes, and multimodal retinal imaging of patients attending four tertiary referring centers with a diagnosis of unilateral CNV in the context of a pre-existing diagnosis of GA were included. GA was assessed on multimodal retinal imaging including spectral-domain optical coherence tomography (SD-OCT) scan with simultaneous near-infrared (NIR) reflectance imaging (OCT Spectralis, Heidelberg Engineering, Heidelberg, Germany) which was acquired at baseline and every follow-up visit. GA area was measured in treated eyes and fellow eyes using NIR. Results: Fifty-four eyes from 27 patients (23 females, mean age 80.89 ± 7.5) were included. The mean number of injections in the treated eyes was 5.52 ± 1.9 by month 12. From baseline to month 12, stabilization of best-corrected visual acuity (BCVA) and a significant decrease (P = .002) of central macular thickness (CMT) in the treated eyes were observed; there was a slight worsening of BCVA (−2 ETDRS letters) and a non-significant change (P = .4) of CMT in the fellow eyes. GA significantly increased in both treated and untreated eyes (P < .001 and P < .001, respectively) with a similar absolute increase (+2.68 mm2 and +2.59 mm2, respectively) and growth rate (0.4 and 0.34, respectively). Conclusions: In our study anti-VEGF treatment for CNV in eyes with pre-existing GA was effective in terms of decrease of exudative changes and stabilization of VA by month 12. A similar growth rate of GA between treated and untreated eyes does not support a causal relationship between anti-VEGF treatment and GA progression in this subset of patients. Further studies with a longer follow-up are mandatory to confirm these results.