Littérature scientifique sur le sujet « Ocular angiogenic disorders »

Vasculogenesis and angiogenesis play a crucial role in embryonic development. Pathological neovascularization in ocular tissues can lead to vision-threatening vascular diseases, including proliferative diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, choroidal neovascularization, and corneal neovascularization. Neovascularization involves various cellular processes and signaling pathways and is regulated by angiogenic factors such as vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF). Modulating these circuits may represent a promising strategy to treat ocular neovascular diseases. Lipid mediators derived from membrane lipids are abundantly present in most tissues and exert a wide range of biological functions by regulating various signaling pathways. In particular, glycerophospholipids, sphingolipids, and polyunsaturated fatty acids exert potent pro-angiogenic or anti-angiogenic effects, according to the findings of numerous preclinical and clinical studies. In this review, we summarize the current knowledge regarding the regulation of ocular neovascularization by lipid mediators and their metabolites. A better understanding of the effects of lipid signaling in neovascularization may provide novel therapeutic strategies to treat ocular neovascular diseases and other human disorders.

Background. Retinal ischemia induces intraocular neovascularization, which often leads to glaucoma, vitreous hemorrhage, and retinal detachment, presumably by stimulating the release of angiogenic molecules. Vascular endothelial growth factor (VEGF) is an endothelial-cell-specific angiogenic factor whose production is increased by hypoxia. Conclusions. Our data suggest that VEGF plays a major part in mediating active intraocular neovascularization in patients with ischemic retinal diseases, such as diabetic retinopathy and retinal-vein occlusion.

Angiogenesis is a complex process that is vital to health but is also a driving factor behind a broad range of malignant, ischaemic, inflammatory, infectious and immune disorders. For optimal efficacy and safety, therapies aimed at preventing angiogenic-mediated disorders must differentiate between healthy and pathological angiogenesis or neovascularisation. Aganirsen is an antisense oligonucleotide that inhibits the insulin receptor substrate (IRS)-1 angiogenic pathway by targeting the IRS-1 messenger RNA. To date, studies of aganirsen have focused mainly on ocular disorders because of the ability to assess non-invasively the effect of the drug on neovascularisation and to address the unmet need for effective therapies in these blinding disorders. Aganirsen (GS-101) eye drops inhibit progressive corneal neovascularisation and appear to be well tolerated. The drug may offer an alternative and/or adjunct to intraocular anti-vascular endothelial cell growth factor (VEGF) agents, which are the current reference standards to prevent neovascularisation in retinal diseases. This is because it has a different and potentially complementary mechanism of action and can be administered topically. Antisense oligonucleotides targeting IRS-1 may present a valuable new approach to control pathological angiogenesis in the eye and elsewhere.

The paper adresses three ocular diseases - “wet” type of age-related macular degeneration, diabetic macular edema and neovascular glaucoma, which have similar neovascular changes and immunological disorders. The key moment of neovascularization development is an imbalance between pro- and anti-angiogenic factors. Particular attention is paid to vascular endothelial growth factor (VEGF-A), pigment epithelial derived factor (PEDF), transforming growth factor-beta (ТGF-β). The paper discusses the “immune privilege” of the eye, ACAID phenomenon, aspects of choroidal neovascularization pathogenesis, inflammation as an important part of neovascularization and the protective response to endogenous and exogenous damage, as well as complement system’s disorders, cytokine status impairment and autoimmune mechanisms. Laser treatment is widely used for treatment of neovascular diseases, but pharmacotherapy is very important too. Anti-angiogenic therapy is extremely promising and is held to provide regression of the newly-formed vasculature and/or normalization of newly formed blood vessels structure and suppress the functional activity of a key proangiogenic factor VEGF-A. Pegaptanib, ranibizumab and bevacizumab are discussed, and results of international clinical trials MARINA, ANCHOR, FOCUS, PrONTO, IVAN, CATT, RESTORE are provided.

Mesenchymal stem cells (MSCs) are adult stem cells that possess the remarkable ability to self-renew and differentiate into various cell lineages. Due to their regenerative potential, MSCs have emerged as the most commonly used stem cell type in clinical applications. Angiogenesis, the formation of new blood vessels, plays a critical role in several pathological conditions, including ocular neovascular diseases, cancer, and inflammatory disorders. Conventional anti-angiogenic therapies face limitations such as frequent visits for repeated doses, off-target effects and resistance development. Recent advances in genetic engineering techniques have opened up novel avenues in regenerative medicine. Genetically engineering MSCs using viral vectors presents a promising strategy to specifically target angiogenesis and enhance anti-angiogenic therapies' efficacy. Viral vectors, including lentiviruses, adeno-associated viruses and adenoviruses, provide an effective means of delivering therapeutic genes into MSCs, allowing the expression of a wide range of therapeutic agents, including anti-angiogenic proteins. This review explores the frontier of using genetically engineered MSCs delivered through viral vectors as a potent anti-angiogenic therapeutic approach. By leveraging the unique properties of MSCs and the targeted delivery capabilities of viral vectors, this approach initiates the potential to revolutionize anti-angiogenic therapy, offering new possibilities for the treatment of angiogenesis-related diseases.

Over the last three decades, there has been special interest in developing drugs that mimic the characteristics of natural tears for use it in the treatment of several ocular surface disorders. Interestingly, the composition of blood plasma is very similar to tears. Therefore, different blood-derived products like autologous serum (AS) and plasma rich in growth factors (PRGF) have been developed for the treatment of diverse ocular pathologies. However, scarce studies have been carried out to analyze the differences between both types of blood-derived products. In the present study, blood from three healthy donors was drawn and processed to obtain AS and PRGF eye drops. Then, human corneal stromal keratocytes (HK) were treated with PRGF or undiluted AS. Proteomic analysis was carried out to analyze and characterize the differential protein profiles between PRGF and AS, and the differentially expressed proteins in HK cells after PRGF and AS treatment. The results obtained in the present study show that undiluted AS induces the activation of different pathways related to an inflammatory, angiogenic, oxidative stress and scarring response in HK cells regarding PRGF. These results suggest that PRGF could be a better alternative than AS for the treatment of ocular surface disorders.

This investigation focused on the design of an injectable nano-enabled thermogel (nano-thermogel) system to attain controlled delivery of p11 anti-angiogenic peptide for proposed effective prevention of neovascularisation and to overcome the drawbacks of the existing treatment approaches for ocular disorders characterised by angiogenesis, which employ multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) antibodies. Synthesis of a polyethylene glycol-polycaprolactone-polyethylene glycol (PEG-PCL-PEG) triblock co-polymer was undertaken, followed by characterisation employing Fourier-transform infrared (FTIR) spectroscopy, nuclear magnetic resonance (NMR) spectroscopy and differential scanning calorimetry (DSC) to ascertain the chemical stability and integrity of the co-polymer instituted for nano-thermogel formulation. The p11 anti-angiogenic peptide underwent encapsulation within poly(lactic-co-glycolic acid) (PLGA) nanoparticles via a double emulsion solvent evaporation method and was incorporated into the thermogel following characterisation by scanning electron microscopy (SEM), zeta size and zeta-potential analysis. The tube inversion approach and rheological analysis were employed to ascertain the thermo-sensitive sol-gel conversion of the nano-thermogel system. Chromatographic assessment of the in vitro release of the peptide was performed, with stability confirmation via Tris-Tricine PAGE (Polyacrylamide Gel Electrophoresis). In vitro biocompatibility of the nano-thermogel system was investigated employing a retinal cell line (ARP-19). A nanoparticle size range of 100–200 nm and peptide loading efficiency of 67% was achieved. Sol-gel conversion of the nano-thermogel was observed between 32–45 °C. Release of the peptide in vitro was sustained, with maintenance of stability, for 60 days. Biocompatibility assessment highlighted 97–99% cell viability with non-haemolytic ability, which supports the potential applicability of the nano-thermogel system for extended delivery of peptide for ocular disorder treatment.

Visual impairment and blindness are common and seriously affect people’s work and quality of life in the world. Therefore, the effective therapies for eye diseases are of high priority. Zebrafish (Danio rerio) is an alternative vertebrate model as a useful tool for the mechanism elucidation and drug discovery of various eye disorders, such as cataracts, glaucoma, diabetic retinopathy, age-related macular degeneration, photoreceptor degeneration, etc. The genetic and embryonic accessibility of zebrafish in combination with a behavioral assessment of visual function has made it a very popular model in ophthalmology. Zebrafish has also been widely used in ocular drug discovery, such as the screening of new anti-angiogenic compounds or neuroprotective drugs, and the oculotoxicity test. In this review, we summarized the applications of zebrafish as the models of eye disorders to study disease mechanism and investigate novel drug treatments.

The global prevalence of eye diseases continues to grow, bringing with it a reduction in the activity levels and quality of life of patients, and partial or complete blindness if left untreated. As such, there is considerable interest in identifying more effective therapeutic options and preventive agents. One such agent is vitamin D, known to have a range of anti-cancer, anti-angiogenic, anti-inflammatory and anti-oxidative properties, and whose deficiency is linked to the pathogenesis of a range of cardiovascular, cancer, and inflammatory diseases. This review presents the current stage of knowledge concerning the link between vitamin D and its receptor and the occurrence of eye disease, as well as the influence of analogues of calcitriol, an active metabolite of vitamin D. Generally, patients affected by various ocular disorders have vitamin D deficiency. In addition, previous findings suggest that vitamin D modulates the course of eye diseases and may serve as a marker, and that its supplementation could mitigate some disorders. However, as these studies have some limitations, we recommend further randomized trials to clarify the link between vitamin D and its activity with eye disease.

Limbal mesenchymal stromal cells (LMSCs) reside in the limbal niche, supporting corneal integrity and facilitating regeneration. While mesenchymal stem/stromal cells (MSCs) are used in regenerative therapies, there is limited knowledge about LMSC subpopulations and their characteristics. This study characterized human LMSC subpopulations through the flow cytometric assessment of fifteen cell surface markers, including MSC, wound healing, immune regulation, ASC, endothelial, and differentiation markers. Primary LMSCs were established from remnant human corneal transplant specimens and passaged eight times to observe changes during subculture. The results showed the consistent expression of typical MSC markers and distinct subpopulations with the passage-dependent expression of wound healing, immune regulation, and differentiation markers. High CD166 and CD248 expressions indicated a crucial role in ocular surface repair. CD29 expression suggested an immunoregulatory role. Comparable pigment-epithelial-derived factor (PEDF) expression supported anti-inflammatory and anti-angiogenic roles. Sustained CD201 expression indicated maintained differentiation capability, while VEGFR2 expression suggested potential endothelial differentiation. LMSCs showed higher VEGF expression than fibroblasts and endothelial cells, suggesting a potential contribution to ocular surface regeneration through the modulation of angiogenesis and inflammation. These findings highlight the heterogeneity and multipotent potential of LMSC subpopulations during in vitro expansion, informing the development of standardized protocols for regenerative therapies and improving treatments for ocular surface disorders.

L'angiogenèse, ou processus de formation de nouveaux vaisseaux sanguins, joue un rôle majeur dans la progression de nombreux cancers et diverses pathologies oculaires. Les récepteurs aux chimiokines CXCR2 sont impliqués dans ces processus en médiant la prolifération cellulaire, l'inflammation et la formation de nouveaux vaisseaux sanguins. Le but de cette thèse a donc été de développer des antagonistes des récepteurs CXCR2 pour inhiber ces mécanismes pathologiques, et en particulier l'angiogenèse pathologique tumorale et oculaire. Sur la base de recherches antérieures, nous avons étudié de nouveaux analogues de N,N'-diarylurée comme inhibiteurs de la voie ELR+CXCL-CXCR2, pour le traitement du cancer. Deux séries d'analogues ont été synthétisées afin d'étudier la relation structure-activité et d'optimiser un composé lead. Des évaluations sur des lignées cellulaires de cancer du rein, de la tête et du cou et de mélanomes uvéaux, ainsi que sur des cultures sphéroïdes 3D ont identifié un composé lead optimisé, montrant une inhibition significative de l'invasion, de la migration et de la néo-angiogenèse. De plus, des études de pharmacologie, de pharmacodynamie et de polymorphisme ont été réalisées. Dans le cadre des pathologies oculaires angiogéniques, le développement d'une seconde famille de composés a été poursuivi, avec notamment l'étude de nouvelles voies de synthèse en vue d'une montée en échelle pour une future production industrielle et des études de formulation afin de réaliser des préparations de principes actifs sous forme de collyre. Enfin, une nouvelle série de composés à visée anticancéreuse a été conçue et une voie de synthèse a été développée pour obtenir une première série d'analogues. L'évaluation des activités biologiques de ces composés a permis de dégager une relation de structure-activité préliminaire
Angiogenesis, the process of forming new blood vessels, plays a crucial role in the progression of various cancers and ocular diseases. CXCR2 chemokine receptors are implicated in these processes by mediating cell proliferation, inflammation, and the formation of new blood vessels. This thesis aims to develop CXCR2 receptor antagonists to inhibit these pathological mechanisms, particularly pathological tumor and ocular angiogenesis. Based on previous research, we investigated new N,N'-diarylurea analogues as inhibitors of the ELR+CXCL-CXCR2 pathway for cancer treatment. Two series of analogues were synthesized to study the structure-activity relationship and to optimize a lead compound. Evaluations on renal, head and neck cancer, and uveal melanoma cell lines, as well as on 3D spheroid cultures, identified an optimized lead compound showing significant inhibition of invasion, migration, and neo-angiogenesis. Additionally, pharmacology, pharmacodynamics, and polymorphism studies were conducted.In the context of ocular angiogenic diseases, the development of a second family of compounds was pursued, including the study of new synthetic routes for scaling up for future industrial production and formulation studies to create active ingredient preparations in the form of eye drops.Finally, a new series of anticancer compounds was designed, and a synthetic route was developed to obtain a first series of analogues. The evaluation of the biological activities of these compounds allowed the establishment of a preliminary structure-activity relationship