Browsing by Subject "Macular degeneration"

Now showing 1 - 4 of 4
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    An improved method for murine laser-induced choroidal neovascularization lesion quantification from optical coherence tomography images
    (Elsevier, 2022-08-02) Jensen, Nathan R.; Lambert-Cheatham, Nathan; Hartman, Gabriella D.; Muniyandi, Anbukkarasi; Park, Bomina; Sishtla, Kamakshi; Corson, Timothy W.; Ophthalmology, School of Medicine
    Laser-induced choroidal neovascularization (L-CNV) in murine models is a standard method for assessing therapies, genetics, and mechanisms relevant to the blinding eye disease neovascular or "wet" age-related macular degeneration. The ex vivo evaluation of these lesions involves confocal microscopy analysis. In vivo evaluation via optical coherence tomography (OCT) has previously been established and allows longitudinal assessment of lesion development. However, to produce robust data, evaluation of many lesions may be required, which can be a slow, arduous process. A prior, manual method for quantifying these lesions as ellipsoids from orthogonal OCT images was effective but time consuming. We therefore developed an OCT lesion quantification that is simplified, streamlined, and less time-consuming.
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    Beyond VEGF: Targeting Inflammation and Other Pathways for Treatment of Retinal Disease
    (American Society for Pharmacology and Experimental Therapeutics, 2023) Muniyandi, Anbukkarasi; Hartman, Gabriella D.; Song, Yang; Mijit, Mahmut; Kelley, Mark R.; Corson, Timothy W.; Ophthalmology, School of Medicine
    Neovascular eye diseases include conditions such as retinopathy of prematurity, proliferative diabetic retinopathy, and neovascular age-related macular degeneration. Together, they are a major cause of vision loss and blindness worldwide. The current therapeutic mainstay for these diseases is intravitreal injections of biologics targeting vascular endothelial growth factor (VEGF) signaling. Lack of universal response to these anti-VEGF agents coupled with the challenging delivery method underscore a need for new therapeutic targets and agents. In particular, proteins that mediate both inflammatory and proangiogenic signaling are appealing targets for new therapeutic development. Here, we review agents currently in clinical trials and highlight some promising targets in preclinical and early clinical development, focusing on the redox-regulatory transcriptional activator APE1/Ref-1, the bioactive lipid modulator soluble epoxide hydrolase, the transcription factor RUNX1, and others. Small molecules targeting each of these proteins show promise for blocking neovascularization and inflammation. The affected signaling pathways illustrate the potential of new antiangiogenic strategies for posterior ocular disease. SIGNIFICANCE STATEMENT: Discovery and therapeutic targeting of new angiogenesis mediators is necessary to improve treatment of blinding eye diseases like retinopathy of prematurity, diabetic retinopathy, and neovascular age-related macular degeneration. Novel targets undergoing evaluation and drug discovery work include proteins important for both angiogenesis and inflammation signaling, including APE1/Ref-1, soluble epoxide hydrolase, RUNX1, and others.
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    Clinical proof of concept for anti-FGF2 therapy in exudative age-related macular degeneration (nAMD): phase 2 trials in treatment-naïve and anti-VEGF pretreated patients
    (Springer Nature, 2024) Pereira, Daniel S.; Maturi, Raj K.; Akita, Kazumasa; Mahesh, Vinaya; Bhisitkul, Robert B.; Nishihata, Toshiaki; Sakota, Eri; Ali, Yusuf; Nakamura, Emiko; Bezwada, Padma; Nakamura, Yoshikazu; Ophthalmology, School of Medicine
    Background/objective: Intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents are the first-line treatment for exudative age-related macular degeneration (nAMD). Due to the limitations of these standard therapies, targeting alternative mechanisms of action may be helpful for treatment of this very common disease. Here, we investigated an anti-fibroblast growth factor-2 (FGF2) aptamer, umedaptanib pegol, a next generation therapeutic for the treatment of nAMD. Methods: Three phase 2 studies were designed. First, a multicentre, randomized, double-masked TOFU study assessed the efficacy of intravitreal injections of umedaptanib pegol monotherapy or in combination with aflibercept, compared to aflibercept monotherapy in 86 subjects with anti-VEGF pretreated nAMD. Second, 22 subjects who had exited the TOFU study received 4 monthly intravitreal injections of umedaptanib pegol (extension, RAMEN study). Third, as an investigator-sponsored trial (TEMPURA study), a single-center, open-label, 4-month study was designed to evaluate the safety and treatment efficacy of umedaptanib pegol in five naïve nAMD patients who had not received any prior anti-VEGF treatment. Results: The TOFU study demonstrated that umedaptanib pegol alone or in combination with aflibercept did not improve best-corrected visual acuity (BCVA) and central subfield thickness (CST) over aflibercept alone. However, the change in BCVA and CST at primary endpoint was marginal in all the three treatment groups, suggesting that umedaptanib pegol is effective to prevent the disease progression. The RAMEN study confirmed the cessation of disease progression. In the TEMPURA study, naïve nAMD patients showed improvement and no further macular degeneration, with striking improvement of visual acuity and central subfield thickness in some of the patients. Conclusions: These results demonstrate, for the first time, clinical proof of concept for aptamer based anti-FGF2 therapy of nAMD.
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    Effects of donor-specific microvascular anatomy on hemodynamic perfusion in human choriocapillaris
    (Springer Nature, 2023-12-19) An, Senyou; Yu, Huidan; Islam, MD Mahfuzul; Zhang, Xiaoyu; Zhan, Yuting; Olivieri, Joseph J.; Ambati, Jayakrishna; Yao, Jun; Gelfand, Bradley D.; Mechanical and Energy Engineering, Purdue School of Engineering and Technology
    Evidence from histopathology and clinical imaging suggest that choroidal anatomy and hemodynamic perfusion are among the earliest changes in retinal diseases such as age-related macular degeneration (AMD). However, how inner choroidal anatomy affects hemodynamic perfusion is not well understood. Therefore, we sought to understand the influences of choroidal microvascular architecture on the spatial distribution of hemodynamic parameters in choriocapillaris from human donor eyes using image-based computational hemodynamic (ICH) simulations. We subjected image-based inner choroid reconstructions from eight human donor eyes to ICH simulation using a kinetic-based volumetric lattice Boltzmann method to compute hemodynamic distributions of velocity, pressure, and endothelial shear stress. Here, we demonstrate that anatomic parameters, including arteriolar and venular arrangements and intercapillary pillar density and distribution exert profound influences on inner choroidal hemodynamic characteristics. Reductions in capillary, arteriolar, and venular density not only reduce the overall blood velocity within choriocapillaris, but also substantially increase its spatial heterogeneity. These first-ever findings improve understanding of how choroidal anatomy affects hemodynamics and may contribute to pathogenesis of retinal diseases such as AMD.