Emerging Concepts in the Treatment of Diabetic Retinopathy

Ellis, Michael; Lent-Schochet, Daniella; Lo, Therlinder; Yiu, Glenn

doi:10.1007/s11892-019-1276-5

Cited by 29 publications

(26 citation statements)

References 94 publications

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“…22–24 Attempts to generate improved therapeutics that capture poor- and non-responders can be broadly divided into two categories, one being the development of alternative and longer-acting anti-VEGFs, while other efforts have focused on alternative targets such as Ang2 and PDGF. 25 It was a search for novel regulators of pathological angiogenesis that led us, through transcriptomic analysis of a number of rodent models of retinal vascular disease, to the discovery of LRG1. 8 In contrast to VEGF, LRG1 is neither required for normal developmental angiogenesis, nor does it appear to have any overt homeostatic role as the null mutant mice are viable, healthy and fertile.…”

Section: Discussionmentioning

confidence: 99%

A Humanized Antibody against LRG1 that Inhibits Angiogenesis and Reduces Retinal Vascular Leakage

Kallenberg

Tripathi

Javaid

et al. 2020

Preprint

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Pathological angiogenesis contributes to morbidity in a number of diseases including cancer, diabetic retinopathy and the neovascular form of age-related macular degeneration, leading to significant efforts to develop effective anti-angiogenic therapeutics for these conditions. The field is dominated by inhibitors of vascular endothelial growth factor (VEGF), yet angiogenesis can also be driven and modified by other factors. We have previously demonstrated that leucine-rich alpha-2-glycoprotein 1 (LRG1) contributes to abnormal vessel growth by activating a TGFß switch. Here we report the development and characterisation of a function-blocking fully humanised IgG4 and its Fab fragment, that bind to LRG1 with high affinity and specificity and inhibit vascular leakage in the mouse model of laser-induced choroidal neovascularisation. In summary, we have developed a therapeutic antibody that targets a VEGF-independent signalling axis, which may be effective in a number of conditions either as monotherapy or in combination with other vascular targeted therapies.

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Section: Discussionmentioning

confidence: 99%

A Humanized Antibody against LRG1 that Inhibits Angiogenesis and Reduces Retinal Vascular Leakage

Kallenberg

Tripathi

Javaid

et al. 2020

Preprint

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“…53 Advances in artificial intelligence show promise in accelerating this process, potentially providing instantaneous feedback on whether the patient requires follow up with an ophthalmologist and even determining which treatment may be indicated. 51,54 These technological advances and the widespread use of telemedicine could also improve access to DR screening for low-middle income countries. Therapeutically, corticosteroids were utilized early in the treatment of DR.…”

Section: Current and Emerging Treatmentsmentioning

confidence: 99%

“… 50 Early and frequent screening is vital as many patients are asymptomatic in the early stages of the disease. 51 The current standard for screening is an ophthalmic exam with pupillary dilation and retinal evaluation. 51 Yet this is still a challenge, especially in low-middle income countries where there may be as few as one ophthalmologist per million people, approximately 1% of the proportion in the United States, and most of these ophthalmologists often live in urban areas, leaving rural patients further underserved.…”

Section: Current and Emerging Treatmentsmentioning

confidence: 99%

“… 51 The current standard for screening is an ophthalmic exam with pupillary dilation and retinal evaluation. 51 Yet this is still a challenge, especially in low-middle income countries where there may be as few as one ophthalmologist per million people, approximately 1% of the proportion in the United States, and most of these ophthalmologists often live in urban areas, leaving rural patients further underserved. 52 However, advances in technology facilitate teleophthalmology, a form of telemedicine, with remote color fundus cameras capable of sending high-quality images to retinal specialists for evaluation.…”

Section: Current and Emerging Treatmentsmentioning

confidence: 99%

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Diabetic Retinopathy in the Aging Population: A Perspective of Pathogenesis and Treatment

Leley¹,

Ciulla²,

Bhatwadekar³

2021

CIA

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The elderly population in the United States is projected to almost double by the year 2050. In addition, the numbers of diabetics are rising, along with its most common complication, diabetic retinopathy (DR). To effectively treat DR within the elderly population, it is essential first to consider the retinal changes that occur due to aging, such as decreased blood flow, retinal thinning, and microglial changes, and understand that these changes can render the retina more vulnerable to oxidative and ischemic damage. Given these considerations, as well as the pathogenesis of DR, specific pathways could play a heightened role in DR progression in elderly patients, such as the polyol pathway and the vascular endothelial growth factor (VEGF) axis. Current ocular treatments include intravitreal corticosteroids, intravitreal anti-VEGF agents, laser photocoagulation and surgical interventions, in addition to better control of underlying diabetes with an expanding range of systemic treatments. While using therapeutics, it is also essential to consider how pharmacokinetics and pharmacodynamics change with aging; oral drug absorption can decrease, and ocular drug metabolism might affect the dosing and delivery methods. Also, elderly patients may more likely be nonadherent to their medication regimen or appointments than younger patients, and undertreatment with anti-VEGF drugs often leads to suboptimal outcomes. With a rising number of elderly DR patients, understanding how aging affects disease progression, pharmacological metabolism, and adherence are crucial to ensuring that this population receives adequate care.

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“…Elevated signaling of vascular endothelial growth factor (VEGF) is most often involved in neovascularization-associated eye diseases. Although antiangiogenic therapies targeting VEGF signaling are generally effective in some of these disease contexts, spontaneous or acquired resistance to anti-VEGF therapies continues to be a significant problem in a substantial percentage of the patient population (;30% in DR and ;10% in wet age-related macular degeneration) because of involvement of other proangiogenic mediators in disease progression (1)(2)(3)(4)(5)(6)(7). Another issue with VEGF signaling inhibition is that VEGF is a trophic factor for vascular endothelial cells (VECs) and neuronal cells (8,9).…”

mentioning

confidence: 99%

Disruption of profilin1 function suppresses developmental and pathological retinal neovascularization

Gau

Vignaud

Allen

et al. 2020

Journal of Biological Chemistry

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Angiogenesis-mediated neovascularization in the eye is usually associated with visual complications. Pathological angiogenesis is particularly prominent in the retina in the settings of proliferative diabetic retinopathy, in which it can lead to permanent loss of vision. In this study, by bioinformatics analyses, we provide evidence for elevated expression of actin-binding protein PFN1 (profilin1) in the retinal vascular endothelial cells (VECs) of individuals with proliferative diabetic retinopathy, findings further supported by gene expression analyses for PFN1 in experimentally induced abnormal retinal neovascularization in an oxygen-induced retinopathy murine model. We observed that in a conditional knockout mouse model, postnatal deletion of the Pfn1 gene in VECs leads to defects in tip cell activity (marked by impaired filopodial protrusions) and reduced vascular sprouting, resulting in hypovascularization during developmental angiogenesis in the retina. Consistent with these findings, an investigative small molecule compound targeting the PFN1–actin interaction reduced random motility, proliferation, and cord morphogenesis of retinal VECs in vitro and experimentally induced abnormal retinal neovascularization in vivo. In summary, these findings provide the first direct in vivo evidence that PFN1 is required for formation of actin-based protrusive structures and developmental angiogenesis in the retina. The proof of concept of susceptibility of abnormal angiogenesis to small molecule intervention of PFN1–actin interaction reported here lays a conceptual foundation for targeting PFN1 as a possible strategy in angiogenesis-dependent retinal diseases.

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Emerging Concepts in the Treatment of Diabetic Retinopathy

Cited by 29 publications

References 94 publications

A Humanized Antibody against LRG1 that Inhibits Angiogenesis and Reduces Retinal Vascular Leakage

A Humanized Antibody against LRG1 that Inhibits Angiogenesis and Reduces Retinal Vascular Leakage

Diabetic Retinopathy in the Aging Population: A Perspective of Pathogenesis and Treatment

Disruption of profilin1 function suppresses developmental and pathological retinal neovascularization

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