Treatment Of Choroidal Neovascularization Research Articles

Light-Activated Anti-Vascular Combination Therapy against Choroidal Neovascularization.

Choroidal neovascularization (CNV) underlies the crux of many angiogenic eye disorders. Although medications that target vascular endothelial growth factor (VEGF) are approved for treating CNV, their effectiveness in destroying new blood vessels is limited, and invasive intravitreal administration is required. Additionally, other drugs that destroy established neovessels, such as combretastatin A-4, may have systemic side effects that limit their therapeutic benefits. To overcome these shortcomings, a two-pronged anti-vascular approach is presented for CNV treatment using a photoactivatable nanoparticle system that can release a VEGF receptor inhibitor and a vascular disrupting agent when irradiated with 690nm light. The nanoparticles can be injected intravenously to enable anti-angiogenic and vascular disrupting combination therapy for CNV through light irradiation to the eyes. This approach can potentiate therapeutic effects while maintaining a favorable biosafety profile for choroidal vascular diseases.

Stable inhibition of choroidal neovascularization by adeno-associated virus 2/8-vectored bispecific molecules.

Neovascular age-related macular degeneration (nAMD) causes severe visual impairment. Pigment epithelium-derived factor (PEDF), soluble CD59 (sCD59), and soluble fms-like tyrosine kinase-1 (sFLT-1) are potential therapeutic agents for nAMD, which target angiogenesis and the complement system. Using the AAV2/8 vector, two bi-target gene therapy agents, AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59, were generated, and their therapeutic efficacy was investigated in laser-induced choroidal neovascularization (CNV) and Vldlr-/- mouse models. After a single injection, AAV2/8-mediated gene expression was maintained at high levels in the retina for two months. Both AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 significantly reduced CNV development for an extended period without side effects and provided efficacy similar to two injections of current anti-vascular endothelial growth factor monotherapy. Mechanistically, these agents suppressed the extracellular signal-regulated kinase and nuclear factor-κB pathways, resulting in anti-angiogenic activity. This study demonstrated the safety and long-lasting effects of AAV2/8-PEDF-P2A-sCD59 and AAV2/8-sFLT-1-P2A-sCD59 in CNV treatment, providing a promising therapeutic strategy for nAMD.

Discriminative atoms embedding relation dual network for classification of choroidal neovascularization in OCT images

Choroidal neovascularization (CNV) is an eye disease that can cause vision loss. Automatic CNV classification in OCT images is crucial in the treatment of CNV. However, two problems arise for CNV classification in OCT images. The subtle visual differences between different CNV types render classification difficult. Additionally, it is difficult to obtain sufficient labeled data, which results in performance degradation. In order to solve these two problems, a discriminative atom-embedding relation dual network is proposed in this paper. Considering that semi-supervised learning (SSL) is an effective machine learning framework to make full use of limited labeled data and a large amount of unlabeled data, the proposed network is developed within an SSL framework. To capture the visual differences, novel discriminative atoms are first introduced to mine discriminative information between different CNV types. Subsequently, a relation module is incorporated to embed the learned discriminative atom information into the features. This makes the learned features capable of distinguishing between different CNV types. Moreover, a novel relation consistency loss is proposed to further improve the robustness of the learned features. Experimental results on private and public datasets demonstrate the effectiveness of the proposed method.

Chorioretinal Atrophic Lesions Evolution in Patients with Quiescent Myopic Choroidal Neovascularization Followed for More Than 10 Years.

To evaluate the progression of chorioretinal atrophic areas associated with myopic choroidal neovascularization (CNV) in high myopic patients followed by a minimum period of 10 years. Patients with myopic CNV lesions that achieved clinical and structural remissions over 10 years of follow-up were included. Medical records were reviewed for CNV characterization and treatment, best-corrected visual acuity at baseline (BCVA0), immediately after the last treatment (BCVA1) and at the latest visit (BCVA2). Fundus autofluorescence (FAF) was used to quantify the amount of atrophic area increase per year associated with the treated myopic CNV lesion. The first FAF performed after treatment suspension (FAF1) was compared with the most recent exam (FAF2). Thirty-six eyes from 36 patients were included. Mean total follow-up was 12.38 ± 2.68 years. Mean number of intravitreal injections (IVI) was 12.50 ± 12.40 and 25% of the eyes had previous treatment with photodynamic therapy (PDT). Mean improvement between BCVA0 and BCVA1 was 5.58 ± 15.98 letters (p < 0.001). However, a drop of 8.03 ± 12.25 letters was noticed between BCVA1 and BCVA2. FAF1 was 6.34 ± 4.92mm2 and increased to 9.88 ± 7.56mm2 (3.54 ± 3.79mm2 variation p < 0.001). The mean growth rate of the atrophic area was 0.89 ± 0.84mm2 per year. BCVA2 negatively correlated with FAF2 (k = -0.498, p = 0.002) being worse in patients with higher atrophic area growth rate (k = -0.341, p = 0.042). Eyes treated with PDT needed less IVI (5.89 ± 5.21 vs 14.70 ± 13.36, p = 0.008) but had larger FAF1 (9.80 ± 5.33 vs 5.19 ± 4.27, p = 0.013) and FAF2 (16.05 ± 7.10 vs 7.83 ± 6.63, p = 0.003). Hypothyroidism was associated with higher atrophy growth rate (1.55 ± 1.15 vs 0.73 ± 0.67, p = 0.016). This research demonstrates the importance of chorioretinal atrophy progression after myopic CNV lesions regression and its impact on visual prognosis, reporting a mean yearly growth of 0.89 mm2 in atrophic areas. Previous treatment with PDT and hypothyroidism were identified as risk factors associated with larger atrophic areas and worse visual outcomes.

Lack of Response to Intravitreal Ranibizumab Treatment in Adult Onset Foveomacular Vitelliform.

Adult-onset foveomacular vitelliform dystrophy (AOFVD) is a rare disease characterized by accumulation of yellowish deposits in the macula. Rarely, it may be complicated by choroidal neovascularization (CNV). Cases with CNV may be confused with occult CNV in age-related macular degeneration. In our case, we will present the visual and anatomical results of a patient with AOVF-related CNV, in which we administered 3 doses of intravitreal ranibizumab (IVR). A 59-year-old female patient, who attended our clinic with the complaint of decreased vision in both eyes, was diagnosed with AOVF-related CNV in both eyes and was treated with 3 doses of IVR for 3 months. Despite the improvement in visual and anatomical functions 1 month after the first dose, vision decreased, and anatomical functions regressed to the pre-injection state in continued injections. IVR therapy is not an appropriate treatment option in the treatment of AOVF-associated CNV.

Pro re nata anti-VEGF treatment in pachychoroid neovasculopathy compared with age-related macular degeneration based on optical coherence tomography.

To compare anti-vascular endothelial growth factor (anti-VEGF) treatment in pachychoroid neovasculopathy (PNV) and age related macular degeneration (AMD). Cases having pro re nata (PRN) anti-VEGF treatment for choroidal neovascularization were reviewed and grouped as PNV and AMD. Groups were compared according to central foveal thickness (CFT), best corrected visual acuity (BCVA), and total injection over 12months. The correlation of beginning choroidal thickness, CFT, and BCVA with final BCVA was analyzed. Forty-seven PNV and 65 AMD cases were reviewed. Both the PNV group (p = 0.0001) and the AMD group (p = 0.003) had a significant improvement in BCVA and a significant decrease in CFT (p = 0.0001). However, BCVA was better at the 3-, 6-, and 12-month follow-up in PNV (p = 0.003, 0.002, 0.02). No significant CFT difference was observed between groups. The total number of injections was 5.7 ± 1.7 for PNV and 5.2 ± 1.5 for AMD (p = 0.09). Beginning BCVA was positively correlated with final BCVA in both groups. The PRN treatment regimen was effective for PNV and AMD in terms of visual and anatomical outcomes. Visual response was better in PNV with PRN treatment with the same number of injections.

Polymeric Propranolol Nanoparticles for Intraocular Delivery: Formulation, Characterization, and Vitreous Pharmacokinetics.

Recent studies have reported the promising effect of intravitreal propranolol on retinal neovascularization. However, rapid clearance and short half-life of the drug in the vitreous are the main drawbacks of this therapeutic approach. This study investigates the extension of the residence time of propranolol in the vitreous by polymeric nanoparticles (NPs) with the prospect of improving choroidal neovascularization treatment. The poly (lactic-co-glycolic) acid (PLGA) NPs were fabricated by a modified double emulsion solvent evaporation method and the obtained NPs were characterized for their size, poly dispersity index (PDI), and surface image. The in vitro release, cell cytotoxicity, and uptake of NPs were also evaluated. To investigate the effect of the vitreous pharmacokinetic drug loaded NPs versus that of the free propranolol, they were intravitreally injected into the rabbits' eyes and the drug vitreous concentrations in defined intervals were analyzed by high performance liquid chromatography (HPLC). The spherical NPs with about 230 nm size, and almost 10% drug loading were obtained. Based on the 3-(4, 5-Dimethylthiazol-2-Yl)-2, 5-Diphenyltetrazolium Bromide (MTT) outcomes, 30 µg/ml of propranolol was considered as the guide dosage in the intravitreal injection. Confocal microscopy images verified the presence of labeled NPs in the posterior segment after five days of receiving the injection. In vivo assay revealed that the vanishing rate of propranolol in rabbits treated with propranolol NPs was reduced at twice the rate as compared to that of the vanishing rate experienced with only the free drug. PLGA NPs can prolong the existence of propranolol in both vitreous and posterior ocular tissues, and thus, may provide an effective approach in treatment of posterior segment neovascularization.

Inactivation of adenosine receptor 2A suppresses endothelial-to-mesenchymal transition and inhibits subretinal fibrosis in mice.

Anti-vascular endothelial growth factor therapy has had a substantial impact on the treatment of choroidal neovascularization (CNV) in patients with neovascular age-related macular degeneration (nAMD), the leading cause of vision loss in older adults. Despite treatment, many patients with nAMD still develop severe and irreversible visual impairment because of the development of subretinal fibrosis. We recently reported the anti-inflammatory and antiangiogenic effects of inhibiting the gene encoding adenosine receptor 2A (Adora2a), which has been implicated in cardiovascular disease. Here, using two mouse models of subretinal fibrosis (mice with laser injury-induced CNV or mice with a deficiency in the very low-density lipoprotein receptor), we found that deletion of Adora2a either globally or specifically in endothelial cells reduced subretinal fibrosis independently of angiogenesis. We showed that Adora2a-dependent endothelial-to-mesenchymal transition contributed to the development of subretinal fibrosis in mice with laser injury-induced CNV. Deficiency of Adora2a in cultured mouse and human choroidal endothelial cells suppressed induction of the endothelial-to-mesenchymal transition. A metabolomics analysis of cultured human choroidal endothelial cells showed that ADORA2A knockdown with an siRNA reversed the increase in succinate because of decreased succinate dehydrogenase B expression under fibrotic conditions. Pharmacological inhibition of ADORA2A with a small-molecule KW6002 in both mouse models recapitulated the reduction in subretinal fibrosis observed in mice with genetic deletion of Adora2a. ADORA2A inhibition may be a therapeutic approach to treat subretinal fibrosis associated with nAMD.

Nonsurgical closure of full thickness macular hole under topical therapy in two eyes with pathologic myopia.

Non-surgical closure of a full-thickness macular hole (FTMH) with eye drops has recently been reported, but there are few similar reports in cases with pathologic myopia. (Case 1) The right eye of a 75-year-old female with an axial length of 28.83 mm had undergone anti-vascular endothelial growth factor (VEGF) treatment for choroidal neovascularization presented with FTMH. Topical betamethasone, bromfenac, and blinzolamide treatments were started, and the FTMH was closed with visual improvement (20/32 to 20/20) after 5 weeks. (Case 2) In the right eye of a 55-year-old male with an axial length of 30.81 mm and lacquer cracks, subretinal hyperreflective material and FTMH developed. The above three drugs were started after anti-VEGF drug injection. Sixteen weeks later, the FTMH was closed with visual improvement (20/63 to 20/20). Nonoperative closure of FTMH has already been reported, but few in eyes with pathologic myopia. Our results suggest that nonoperative closure of FTMH associated with pathologic myopia under eye drops may be possible in some cases.

Angioid Streaks Remain a Challenge in Diagnosis, Management, and Treatment.

Aim: Angioid streaks (ASs) are a rare retinal condition and compromise visual acuity when complicated with choroidal neovascularization (CNV). They represent crack-like dehiscences at the level of the Bruch's membrane. This objective narrative review aims to provide an overview of pathophysiology, current treatment modalities, and future perspectives on this condition. Materials and Methods: A literature search was performed using "PubMed", "Web of Science", "Scopus", "ScienceDirect", "Google Scholar", "medRxiv", and "bioRxiv." Results: ASs may be idiopathic, but they are also associated with systemic conditions, such as pseudoxanthoma elasticum, hereditary hemoglobinopathies, or Paget's disease. Currently, the main treatment is the use of anti-vascular endothelial growth factors (anti-VEGF) to treat secondary CNV, which is the major complication observed in this condition. If CNV is detected and treated promptly, patients with ASs have a good chance of maintaining functional vision. Other treatment modalities have been tried but have shown limited benefit and, therefore, have not managed to be more widely accepted. Conclusion: In summary, although there is no definitive cure yet, the use of anti-VEGF treatment for secondary CNV has provided the opportunity to maintain functional vision in individuals with AS, provided that CNV is detected and treated early.

5-Aza-2'-Deoxycytidine Ameliorates Choroidal Neovascularization by Inhibiting the Wnt/β-Catenin Signaling Pathway.

Choroidal neovascularization (CNV) can constitute the final pathology of many ocular diseases and result in severe vision loss. Studies have demonstrated that DNA methylation is critical in retinal development, aging, and disorders. The current work investigated the effects and underlying mechanism of 5-Aza-2'-deoxycytidine (5-aza-dC), a suppressor of DNA methylation, in the pathological progression of CNV. The DNA methylation profiles of retinal pigment epithelial (RPE)/choroidal complexes in normal and laser-induced CNV mice were assessed by Arraystar Mouse RefSeq Promoter Arrays. The CNV area and blood flow density and intensity were observed by optical coherence tomography angiography, and fluorescence leakage was examined by fundus fluorescein angiography in CNV mice with systemic administration of 5-aza-dC. The effects of 5-aza-dC on the biological functions of bEnd.3 cells were estimated by related assays. Notum gene promoter methylation was measured using bisulfite sequencing PCR. Methyltransferases and Wnt signaling-related genes were detected in animal and cell culture experiments by real-time PCR and immunoblot. Methyltransferases were upregulated, but Notum (a secretion inhibitor of Wnt signaling) was downregulated in the RPE/choroidal complexes of mice with experimental CNV. Intraperitoneal injection of 5-aza-dC inactivated the Wnt pathway and ameliorated the lesion area and the intensity and density of blood flow, as well as the degree of leakage in CNV. In vitro, vascular endothelial growth factor A (VEGFA) stimulation promoted methyltransferases expression and suppressed Notum expression, consequently activating Wnt signaling, whereas exogenous 5-aza-dC reversed VEGFA-induced hyperpermeability, proliferation, migration, and tube formation in bEnd.3 cells via demethylation of Notum promoter. We observed that 5-aza-dC attenuates the growth of CNV by inhibiting the Wnt signaling pathway via promoter demethylation of the Wnt antagonist Notum. These findings provide a theoretical basis for methylation-based treatment with the Notum gene as a potential target for CNV treatment.

CHOROIDAL NEOVASCULARIZATION IN A CHILD WITH DOWN SYNDROME

Purpose: To report a case of Down syndrome with myopic choroidal neovascularization (CNV) and the treatment outcome. Methods: Case report. Main outcome measures include refractive error, fundus examination, optical coherence tomography (OCT), OCT angiography (OCTA), fluorescein angiography (FA), anti-vascular endothelial growth factor (VEGF) injections. Results: A 12-year-old boy with Down syndrome presented at a regular check-up with decreased visual acuity (VA) with macular degeneration in the left eye. The best-corrected VA was 0.6 in the right eye and 0.1 in the left eye, which decreased from 0.3 1 year ago. The refractive error (spherical equivalent) was -5.25 diopters (D) in the right eye and -8.00 D in the left eye. Detailed examinations were performed under general anesthesia. The fundus examination showed macular degeneration with retinal pigment epithelium (RPE) atrophy, pigmentary changes, and fibrous tissue in the left eye. OCT showed CNV at the macula with edema, and OCTA showed spreading CNV above the RPE at the macula in the left eye. FA showed hyperfluorescence in the early phase and late dye leakage from the CNV. Intravitreal ranibizumab injections were administered twice within 2 months, and he maintained a VA of 0.1 in the left eye. Conclusion: CNV and associated macular degeneration may occur in Down syndrome with high myopia possibly because of the abnormal choroidal structure. In children with Down syndrome, regular fundus examinations with OCT are important for early detection and treatment of CNV.

Crocetin inhibits choroidal neovascularization in both in vitro and in vivo models

Choroidal neovascularization (CNV) is the primary pathogenic process underlying wet age-related macular degeneration, leading to severe vision loss. Despite current anti-vascular endothelial growth factor (VEGF) therapies, several limitations persist. Crocetin, a major bioactive constituent of saffron, exhibits multiple pharmacological activities, yet its role and mechanism in CNV remain unclear. Here, we investigated the potential effects of crocetin on CNV using in vitro and in vivo models. In human umbilical vein endothelial cells, crocetin demonstrated inhibition of VEGF-induced cell proliferation, migration, and tube formation in vitro, as assessed by CCK-8 and EdU assays, transwell and scratch assays, and tube formation analysis. Additionally, crocetin suppressed choroidal sprouting in ex vivo experiments. In the human retinal pigment epithelium (RPE) cell line ARPE-19, crocetin attenuated cobalt chloride-induced hypoxic cell injury, as evidenced by CCK-8 assay. As evaluated by quantitative PCR and Western blot assay, it also reduced hypoxia-induced expression of VEGF and hypoxia-inducible factor 1α (HIF-1α), while enhancing zonula occludens-1 expression. In a laser-induced CNV mouse model, intravitreal administration of crocetin significantly reduced CNV size and suppressed elevated expressions of VEGF, HIF-1α, TNFα, IL-1β, and IL-6. Moreover, crocetin treatment attenuated the elevation of phospho-S6 in laser-induced CNV and hypoxia-induced RPE cells, suggesting its potential anti-angiogenic effects through antagonizing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Our findings indicate that crocetin may hold promise as an effective drug for the prevention and treatment of CNV.

ANATOMICAL AND FUNCTIONAL OUTCOMES OF BEVACIZUMAB TREATMENT IN PEDIATRIC AUTOSOMAL RECESSIVE BESTROPHINOPATHY.

The purpose of this study was to report functional and anatomical outcomes of anti-VEGF treatment in eyes with autosomal recessive bestrophinopathy (ARB) presenting in the first decade of life. The study included case series of four eyes from two siblings with compound heterozygous mutations in the BEST1 gene who were treated with eight monthly intravitreal bevacizumab injections. Response to treatment was analyzed using color fundus photography, fundus autofluorescence, optical coherence tomography, OCT angiography, and microperimetry. Patient 1 (male, age 9 years) had visual acuity of 20/20 in the right eye and 20/50 in the left eye. Patient 2 (female, age 10 years) had visual acuity of 20/25 in the right eye and 20/20 in the left eye. All eyes had multifocal subretinal deposition of lipofuscin and subretinal fluid, and three eyes had choroidal neovascularization (CNV). Lipofuscin material reabsorbed in 2 of 4 eyes, the CNV regressed in 3 of 3 eyes, a bacillary detachment resolved in 1 of 1 eye, but the subretinal fluid did not change. Functional improvement in visual acuity was noted, but MP showed scattered areas of reduced retinal sensitivity. No ocular or systemic side effects were detected. Anti-VEGF treatment of choroidal neovascularization in eyes with ARB resulted in anatomical changes that were only clinically significant in the eye with decreased visual acuity. The hyporeflective subretinal material remained unchanged suggesting a nonexudative cause. These findings provide new insights into the management of ARB, especially in pediatric subjects with CNV.

Targeted long-term noninvasive treatment of choroidal neovascularization by biodegradable nanoparticles.

Choroidal neovascularization (CNV) is the main cause of vision loss in patients with wet age-related macular degeneration (AMD). Currently, treatment of these conditions requires repeated intravitreal injections, which may lead to complications such as infection and hemorrhage. So, we have developed a noninvasive method for treating CNV with nanoparticles, namely, Angiopoietin1-anti CD105-PLGA nanoparticles (AAP NPs), which targets the CNV to enhance drug accumulation at the site. These nanoparticles, with PLGA as a carrier, can slowly release encapsulated Angiopoietin 1 (Ang 1) and target the choroidal neovascularization marker CD105 to enhance drug accumulation, increases vascular endothelial cadherin (VE-cadherin) expression between vascular endothelial cells, effectively reduce neovascularization leakage and inhibit Angiopoietin 2(Ang 2) secretion by endothelial cells. In a rat model of laser-induced CNV, intravenous injection of AAP NPs exerted a good therapeutic effect in reducing CNV leakage and area. In short, these synthetic AAP NPs provide an effective alternative treatment for AMD and meet the urgent need for noninvasive treatment in neovascular ophthalmopathy. STATEMENT OF SIGNIFICANCE: This work describes the synthesis, injection-mediated delivery, in vitro and in vivo efficacy of targeted nanoparticles with encapsulated Ang1; via these nanoparticles, the drug can be targeted to choroidal neovascularization lesions for continuous treatment. The release of Ang1 can effectively reduce neovascularization leakage, maintain vascular stability, and inhibit Ang2 secretion and inflammation. This study provides a new approach for the treatment of wet age-related macular degeneration.

Efficacy and safety of different conbercept injection regimens in the treatment of choroidal neovascularization in pathological myopia: a retrospective study.

To investigate the clinical efficacy of conbercept 1 + pro re nata (PRN) (i.e., reinjection as needed after one injection) and 3 + PRN (reinjection as needed after 3months of injection) regimens in choroidal neovascularization secondary to pathological myopia (PM-CNV). From 06/2019 to 06/2020, 65 patients (65 eyes) confirmed with PM-CNV were included in this retrospective study. Intravitreal injection of 0.5mg conbercept was conducted either with the 1 + PRN or 3 + PRN strategy. Patients were followed up for 12months. The best-corrected visual acuity (BCVA), central retinal thickness (CRT), CNV lesion leakage area, the number of injections, and postoperative adverse reactions were observed. The mean age of the patients was 42.10 ± 4.69years, and the average diopter was -11.26 ± 2.97D. The BCVA at month 3 in the 3 + PRN (n = 30) group was lower than in the 1 + PRN (n = 35) group (P < 0.001). The CRT at month 3 in the 3 + PRN group was lower than in the 1 + PRN group (P < 0.001). After 12months, there were no differences in the BCVA and CRT between the two groups (P > 0.05). The number of injections was less in 1 + PRN than in 3 + PRN (2.14 ± 1.06 vs. 3.37 ± 0.76, P < 0.001) at 12months. No serious treatment-related ocular complications or serious systemic adverse events were found. The 1 + PRN and 3 + PRN strategies of intravitreal injection of conbercept are effective in treating PM-CNV. The 1 + PRN regimen required fewer injections, and it might be more suitable for the treatment of PM-CNV.

Intravitreal CendR peptides target laser-induced choroidal neovascularization sites in mice

Choroidal neovascularization (CNV) is a common ocular pathology that may be associated in a variety of eye diseases. Although intravitreal injection treatment of anti-vascular endothelial growth factor (anti-VEGF) drugs shows significant clinical benefits in CNV treatment, the limitations of the current therapy need to be addressed. The aim of our study was to investigate the potential utility of three C-end Rule (CendR) peptides (RPARPAR, PL3, iRGD) for CNV targeting and to evaluate the efficacy of peptides for treating experimental CNV in mice. We observed that the CendR peptides localize to the CNV lesion sites after intravitreal injection and were mainly found in the outer nuclear cell layer (ONL) of the mouse retina. Interestingly, experimental therapy with tenascin-C (TNC-C) and neuropilin-1 (NRP-1)-targeting PL3 peptide, reduced angiogenesis and decreased vascular leakage. The results suggest that PL3 and potentially other CendR peptides could serve as affinity targeting ligands and therapeutics for ocular diseases that involve pathological CNV.

A novel retinoic acid drug, EYE-502, inhibits choroidal neovascularization by targeting endothelial cells and pericytes

Choroidal neovascularization (CNV) occurs in neovascular age-related macular degeneration (AMD) and often leads to permanent visual impairment. Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is the gold standard for the treatment of CNV. However, anti-VEGF treatment did not always cause vision improvement and sometimes had detrimental effects on normal retinal tissues. Herein, we identified a novel retinoic acid drug, EYE-502, which had great therapeutic effects on CNV. Administration of EYE-502 could inhibit VEGF-induced dysfunction of endothelial cells (ECs) and reduce platelet-derived growth factor (PDGF)-induced recruitment of pericytes to ECs in vitro. Administration of EYE-502 could reduce the area of choroidal sprouting and laser-induced CNV, exhibiting similar anti-angiogenic effects as aflibercept. Moreover, administration of EYE-502 could reduce pericyte coverage in the sprouting vessels and choroidal neovascularization. Mechanistically, EYE-502 primarily bound to retinoic acid receptors (RARs) and exerted the anti-angiogenic effects by targeting ECs and pericytes via affecting the activation of Wnt/β-catenin and PDGF/PDGFR/PI3K/Akt signaling. Taken together, this study reports a novel retinoic acid drug, EYE-502, which can exert the anti-angiogenic effects by simultaneous targeting of ECs and pericytes.

3K3A-Activated Protein C Inhibits Choroidal Neovascularization Growth and Leakage and Reduces NLRP3 Inflammasome, IL-1β, and Inflammatory Cell Accumulation in the Retina.

3K3A-Activated Protein C (APC) is a recombinant variant of the physiological anticoagulant APC with cytoprotective properties and reduced bleeding risks. We studied the potential use of 3K3A-APC as a multi-target therapeutic option for choroidal neovascularization (CNV), a common cause of vision loss in age-related macular degeneration. CNV was induced by laser photocoagulation in a murine model, and 3K3A-APC was intravitreally injected. The impact of 3K3A-APC treatment on myeloid and microglia cell activation and recruitment and on NLRP3 inflammasome, IL-1β, and VEGF levels was assessed using cryosection, retinal flat-mount immunohistochemistry and vascular imaging. Additionally, we evaluated the use of fluorescein angiography as a surrogate marker for in vivo evaluation of the efficacy of 3K3A-APC treatment against leaking CNV lesions. Our results demonstrated that 3K3A-APC treatment significantly reduced the accumulation and activation of myeloid cells and microglia in the CNV area and decreased the NLRP3 and IL-1β levels at the CNV site and the surrounding retina. Furthermore, 3K3A-APC treatment resulted in leakage regression and CNV growth suppression. These findings indicate that the anti-inflammatory activities of 3K3A-APC contribute to CNV inhibition. Our study suggests the potential use of 3K3A-APC as a novel multi-target treatment for CNV.

Choroidal neovascularization removal with photo-mediated ultrasound therapy.

Age-related macular degeneration (AMD) is a major cause of irreversible central vision loss. The main reason for lost vision due to AMD is choroidal neovascularization (CNV). In the clinic, current treatments for CNV include photodynamic therapy, laser photocoagulation, and anti-vascular endothelial growth factor (VEGF) therapy. This study evaluates a novel treatment technique combining synchronized nanosecond laser pulses and ultrasound bursts, namely photo-mediated ultrasound therapy (PUT) as a potential treatment method for CNV, for its efficacy and safety in the treatment of CNV via the experiments in a clinically-relevant rabbit model in vivo. CNV was created by subretinal injection of Matrigel and vascular endothelial growth factor (M&V) in 10 New Zealand white rabbits. Six rabbits were used in the PUT group. In the control groups, two rabbits were treated by laser-only, and two rabbits were treated by ultrasound-only. The treatment efficacy was evaluated through fundus photography and fluorescein angiography (FA) longitudinally for up to 4weeks. Rabbits were sacrificed for histopathology 3 months after treatment to examine the safety of PUT. The fluorescein leakage on FA was quantified to longitudinally evaluate treatment outcome. Compared with baseline, the relative intensity index was reduced by 26.57%±8.66% at 3 days after treatment, 27.24%±6.21% at 1week after treatment, 27.79%±2.61% at 2weeks after treatment, and 32.12%±3.23% at 4weeks after treatment, all with a statistically significant difference of p<0.01. The comparison between the relative intensity indexes from the two control groups (laser-only treatment and ultrasound-only treatment) did not show any statistically significant difference at all time points. Safety evaluation at 3 months with histopathology demonstrated that the PUT did not result in morphologic changes to the neurosensory retina. This study introduces PUT for the first time for the treatment of CNV. The results demonstrated good efficacy and safety of PUT to treat CNV in a clinically-relevant rabbit model. With a single session of treatment, PUT can safely reduce the leakage of CNV for at least 1 month after treatment.