Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

Wallsh, Josh; Gallemore, Ron P.

doi:10.3390/cells10051049

Cited by 75 publications

(70 citation statements)

References 167 publications

(167 reference statements)

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“…Current treatments include the use of anti-VEGF agents, which improve visual acuity in 25–30% of DR patients [ 102 , 107 , 108 ]. Anti-VEGF therapy for DME results in a decrease in fluid leakage and can be sufficient to restore vision in DME patients [ 106 , 109 ]. Laser photocoagulation is also used for treatment of PDR and DME [ 104 ].…”

Section: Neovascular Eye Diseasesmentioning

confidence: 99%

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

Hartman

Lambert-Cheatham

Kelley

et al. 2021

IJMS

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Proliferative diabetic retinopathy (PDR), neovascular age-related macular degeneration (nvAMD), retinopathy of prematurity (ROP) and other eye diseases are characterized by retinal and/or choroidal neovascularization, ultimately causing vision loss in millions of people worldwide. nvAMD and PDR are associated with aging and the number of those affected is expected to increase as the global median age and life expectancy continue to rise. With this increase in prevalence, the development of novel, orally bioavailable therapies for neovascular eye diseases that target multiple pathways is critical, since current anti-vascular endothelial growth factor (VEGF) treatments, delivered by intravitreal injection, are accompanied with tachyphylaxis, a high treatment burden and risk of complications. One potential target is apurinic/apyrimidinic endonuclease 1/reduction-oxidation factor 1 (APE1/Ref-1). The multifunctional protein APE1/Ref-1 may be targeted via inhibitors of its redox-regulating transcription factor activation activity to modulate angiogenesis, inflammation, oxidative stress response and cell cycle in neovascular eye disease; these inhibitors also have neuroprotective effects in other tissues. An APE1/Ref-1 small molecule inhibitor is already in clinical trials for cancer, PDR and diabetic macular edema. Efforts to develop further inhibitors are underway. APE1/Ref-1 is a novel candidate for therapeutically targeting neovascular eye diseases and alleviating the burden associated with anti-VEGF intravitreal injections.

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Section: Neovascular Eye Diseasesmentioning

confidence: 99%

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

Hartman

Lambert-Cheatham

Kelley

et al. 2021

IJMS

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“…However, intense research is being carried out targeting these pathologies using a wide variety of approaches [58][59][60][61][62][63]. Current strategies focus on slowing down or stop the initial triggers (e.g., AREDS supplementation, exercise, eating well, and smoking cessation in dry AMD, and anti-VEGF intraocular injections in wet AMD) [64,65], or focus on relieving the symptoms (e.g., lowering intraocular pressure (IOP) with prostaglandin analogues or beta blockers in glaucoma) [66]. Given the wide expression profile of the eCB system in the neuro-retina, the use of this system as a pharmacological target, particularly the typical and atypical cannabinoid receptors, in the management of these retinal diseases is of great interest.…”

Section: Cannabinoid Receptors In Retinal Diseasesmentioning

confidence: 99%

The Vertical and Horizontal Pathways in the Monkey Retina Are Modulated by Typical and Atypical Cannabinoid Receptors

Bouskila

Bleau

Micaelo-Fernandes

et al. 2021

Cells

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The endocannabinoid (eCB) system has been found in all visual parts of the central ner-vous system and plays a role in the processing of visual information in many species, including monkeys and humans. Using anatomical methods, cannabinoid receptors are present in the monkey retina, particularly in the vertical glutamatergic pathway, and also in the horizontal GABAergic pathway. Modulating the eCB system regulates normal retinal function as demonstrated by electrophysiological recordings. The characterization of the expression patterns of all types of cannabinoid receptors in the retina is progressing, and further research is needed to elucidate their exact role in processing visual information. Typical cannabinoid receptors include G-protein coupled receptor CB1R and CB2R, and atypical cannabinoid receptors include the G-protein coupled receptor 55 (GPR55) and the ion channel transient receptor potential vanilloid 1 (TRPV1). This review focuses on the expression and localization studies carried out in monkeys, but some data on other animal species and humans will also be reported. Furthermore, the role of the endogenous cannabinoid receptors in retinal function will also be presented using intraocular injections of known modulators (agonists and antagonists) on electroretinographic patterns in monkeys. The effects of the natural bioactive lipid lysophosphatidylglucoside and synthetic FAAH inhibitor URB597 on retinal function, will also be described. Finally, the potential of typical and atypical cannabinoid receptor acti-vity regulation in retinal diseases, such as age-related macular degeneration, diabetic retinopathy, glaucoma, and retinitis pigmentosa will be briefly explored.

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“… 17 , 18 Steroid injections, laser treatment, and anti-VEGF agents are currently used therapies for most retinal diseases and are selected based on the clinical scenario. 19 The most common route of delivering the macromolecules to the posterior segment requires frequent intravitreal injections that carry a risk of serious adverse effects. 13 , 14 Intravitreal injection of anti-VEGF requires a monthly injection, which can lead to patient discomfort, increase chance of postinjection infections, and related complications.…”

Section: Introductionmentioning

confidence: 99%

“… 20 – 22 Steroids implants, such as intravitreal triamcinolone (IVTA), Dexamethasone (DEX), and fluocinolone acetonide (FA), are all effective in the treatment of retinal vascular diseases. 19 DEX implants are also effective for the treatment of diabetic retinopathy as an alternative and/or in combination with anti-VEGF therapy. 23 – 27 Previous studies have shown that DEX intravitreal implants can deliver a sustainable release of macromolecules into the eye, which can help control the severity of diabetic macular edema (DME) and complications after vitrectomy surgery.…”

Section: Introductionmentioning

confidence: 99%

“… 28 Laser therapies have become a second-line therapy when patients have poorly controlled glaucoma or fail to respond to steroid therapies. 19 These methods can be invasive and often require long-term repeated therapy. 1 – 4 , 29 Furthermore, they may present a significant financial and time-consuming burden on both the patients and the medical system.…”

Section: Introductionmentioning

confidence: 99%

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Feasibility of Therapeutic Ultrasound Application in Topical Scleral Delivery of Avastin

Almogbil

Nasrallah

Zderic

2021

Trans. Vis. Sci. Tech.

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Purpose Macromolecules have been shown to be effective in vision-saving treatments for various ocular diseases, such as age-related macular degeneration and diabetic retinopathy. The current delivery of macromolecules requires frequent intraocular injections and carries a risk of serious adverse effects. Methods We tested the application of therapeutic ultrasound as a minimally invasive approach for the delivery of Avastin into the diseased regions of the eye. Avastin (bevacizumab) is an anti-vascular endothelial growth factor (VEGF) antibody with a molecular weight of 149 kDa. We tested the effectiveness and safety of Avastin delivery through rabbit sclera in vitro using a standard diffusion cell model. Ultrasound at frequencies of 400 kHz or 3 MHz with an intensity of 1 W/cm 2 was applied for the first 5 minutes of 1-hour drug exposure. Sham treatments mimicked the ultrasound treatments, but ultrasound was not turned on. Absorbance measurements of the receiver compartment solution were performed at 280 nm using a spectrophotometer. Results Absorbance measurements indicated no statistical difference between the sham ( n = 13) and 400 kHz ultrasound group ( n = 15) in the delivery of Avastin through the sclera. However, the absorbance values were statistically different ( P < 0.01) between the 3 MHz ultrasound group (0.004, n = 8) and the matched sham group (0.002, n = 7). There was 2.3 times increase in drug delivery in the 3 MHz ultrasound when compared to the corresponding sham group. Histological studies indicated no significant damage in the ultrasound-treated sclera due to ultrasound application. Conclusions Our preliminary results provided support that therapeutic ultrasound may be effective in the delivery of Avastin through the sclera. Translational Relevance Our study offers clinical potential for a minimally invasive retinopathy treatment.

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Anti-VEGF-Resistant Retinal Diseases: A Review of the Latest Treatment Options

Cited by 75 publications

References 167 publications

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

Inhibition of APE1/Ref-1 for Neovascular Eye Diseases: From Biology to Therapy

The Vertical and Horizontal Pathways in the Monkey Retina Are Modulated by Typical and Atypical Cannabinoid Receptors

Feasibility of Therapeutic Ultrasound Application in Topical Scleral Delivery of Avastin

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