Sema3A Antibody BI-X Prevents Cell Permeability and Cytoskeletal Collapse in HRMECs and Increases Tip Cell Density in Mouse Oxygen-Induced Retinopathy

Zippel, Nina; Kenny, Cynthia Hess; Wu, Helen; Garneau, Michel; Kroe‐Barrett, Rachel; Gupta, Priyanka; Low, Seng Hui; Bakker, Remko A.; Thomas, Leo H.

doi:10.1167/tvst.11.6.17

Cited by 9 publications

(9 citation statements)

References 29 publications

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“…This conjecture is supported by our finding that, when compared with aflibercept, intravitreal administration of BI-Y into the eye of mice with OIR significantly reduces the size of the avascular area and significantly increases tip cell density at the avascular front. These results align with previous work demonstrating the central role of Sema3A and Nrp-1 in angiogenesis and endothelial leakage using mouse models (Fantin et al, 2014, Fernández-Robredo et al, 2017, Nakamura et al, 2022, Zippel et al, 2022.…”

Section: Bi-y Does Not Affect Vegf-a-dependent Laser-induced Choroidalsupporting

confidence: 92%

“…expression, and Zippel et al showed that application of a Sema3A neutralizing antibody (referred to as BI-X) in an OIR resulted in a significant negative correlation between tip cell density and size of the avascular area and a trend for reduction of the avascular area (Nakamura et al, 2022, Zippel et al, 2022; i.e. the effects of the two antibodies are qualitatively similar.…”

Section: Nakamura Et Al Found That Induction Of Vein Occlusion Signif...mentioning

confidence: 99%

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BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies

Thomas

Low

Hansen

et al. 2023

J Pharmacol Exp Ther

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Diabetic retinopathy (DR) is a leading cause of vision loss in working-age adults. Despite an established standard of care for advanced forms of DR, some patients continue to lose vision following treatment. This may be due to the development of diabetic macular ischemia (DMI), which has no approved treatment. Neuropilin-1 (Nrp-1) is a co-receptor with two ligand-binding domains, with semaphorin-3A (Sema3A) binding to the A domain and vascular endothelial growth factor-A (VEGF-A) binding to the B-domain. Sema3A directs a subset of neuronal growth cones as well as blood vessel growth by repulsion; when bound to Nrp-1, VEGF-A mediates vascular permeability and angiogenesis. Modulating Nrp-1 could therefore address multiple complications arising from DR, such as diabetic macular edema (DME) and DMI. BI-Y is a monoclonal antibody that binds to the Nrp-1 A-domain, antagonizing the effects of the ligand Sema3A and inhibiting VEGF-A-induced vascular permeability. This series of in vitro and in vivo studies examined the binding kinetics of BI-Y to Nrp-1 with and without VEGF-A 165 , the effect of BI-Y on Sema3A-induced cytoskeletal collapse, the effect of BI-Y on VEGF-A 165 -induced angiogenesis, neovascularization, cell integrity loss and permeability, and on retinal revascularization. The data show that BI-Y binds to Nrp-1 and inhibits Sema3A-induced cytoskeletal collapse in vitro, may enhance revascularization of ischemic areas in an oxygen-induced retinopathy mouse model, and prevents VEGF-A-induced retinal hyperpermeability in rats. However, BI-Y does not interfere with VEGF-A-dependent choroidal neovascularization. These results support further investigation of BI-Y as a potential treatment for DMI and DME.

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Section: Bi-y Does Not Affect Vegf-a-dependent Laser-induced Choroidalsupporting

confidence: 92%

Section: Nakamura Et Al Found That Induction Of Vein Occlusion Signif...mentioning

confidence: 99%

BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies

Thomas

Low

Hansen

et al. 2023

J Pharmacol Exp Ther

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“…Silencing expression of Sema3A in a mouse model of oxygen-induced retinopathy has been shown to maintain neuroretinal function [33]. Furthermore, recent data show that administration of the anti-Sema3A agent BI 764524 in a mouse model of oxygen-induced retinopathy significantly reduces avascular area size [27] and had a beneficial effect on intraretinal oedema and ischaemia in a retinal vein occlusion mouse model [34]. This suggests that Sema3A plays a targetable and pathological role in retinal ischaemia by contributing to vascular and subsequently neuronal damage, ultimately resulting in progressive vision loss.…”

Section: Discussionmentioning

confidence: 99%

“…BI 764524 is an intravitreal anti-Sema3A ischaemia modulator agent. Preclinical data show that BI 764524 reduces the area of ischaemia in mouse retinas with oxygen-induced retinopathy [27]. HORNBILL is the first clinical trial assessing a treatment for DMI and the first trial to use OCTA as a means to define and examine DMI.…”

Section: Background and Rationale {6a}mentioning

confidence: 99%

HORNBILL: a phase I/IIa trial examining the safety, tolerability and early response of BI 764524 in patients with diabetic retinopathy and diabetic macular ischaemia—rationale, study design and protocol

Chong

Nguyen

Sepah

et al. 2022

Trials

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Background Diabetic macular ischaemia (DMI) is a complication of diabetic retinopathy that leads to irreversible vision loss. DMI is characterised by reduced retinal vessel density and enlargement of the foveal avascular zone (FAZ). Despite its clinical burden, there is no formal consensus on the definition of DMI, and no approved treatment. Semaphorin 3A (Sema3A) is an axonal guidance molecule that blocks revascularisation of the ischaemic retina. Sema3A modulation is therefore a promising mechanism of action for the treatment of ischaemic eye diseases. BI 764524 is an intravitreal anti-Sema3A ischaemia modulator agent. Methods HORNBILL (NCT04424290) is a phase I/IIa trial comprising a non-randomised, open-label, single rising dose (SRD) part and a randomised, masked, sham-controlled multiple dose (MD) part to investigate the safety, tolerability and early biological response of ischaemia modulator BI 764524 in adults (≥18 years) with DMI. DMI will be defined using optical coherence tomography angiography (OCTA) as either any degree of disruption in the retinal vascularity (SRD) or a FAZ of ≥0.5 mm2 (MD). Subjects in the SRD part will receive 0.5, 1.0 or 2.5 mg of BI 764524; the maximum tolerated dose will then be used in the MD part. A minimum of 12 subjects will be enrolled into the SRD part; planned enrollment is 30 for the MD part. The primary endpoint of the SRD part is the number of subjects with dose-limiting adverse events (AEs) until day 8. The primary endpoint of the MD part is the number of subjects with drug-related AEs from baseline to end of study, and secondary endpoints include change from baseline in the size of the FAZ, best-corrected visual acuity and central retinal thickness. Discussion DMI is a poorly defined condition with no treatment options. HORNBILL is the first clinical trial to assess a treatment for DMI and to use OCTA as a means to define and examine DMI. The OCTA data generated in this trial could form the basis of formal diagnostic criteria for DMI. Furthermore, the novel mechanism of action (Sema3A modulation) explored in this trial has the potential to revolutionise the treatment landscape for patients with DMI. Trial registration ClinicalTrials.govNCT04424290; EudraCT 2019-004432-28. Registered on 9 June 2020

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“…Sema6A inhibits the formation of endothelial cells. Consequently, when the expression of sema6A in the retina or vitreous decreases, the production and number of new endothelial cells increases, thereby increasing their content in the vitreous and decreasing the clarity of the vitreous [ 103 , 104 ] (Nina et al, 2022; Guo et al, 2019).…”

Section: Application Of Proteomics In Optic Nerve Injury Diseasesmentioning

confidence: 99%

Application of Proteomics Analysis and Animal Models in Optic Nerve Injury Diseases

et al. 2023

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Optic nerve damage is a common cause of blindness. Optic nerve injury is often accompanied by fundus vascular disease, retinal ganglion cell apoptosis, and changes in retinal thickness. These changes can cause alterations in protein expression within neurons in the retina. Proteomics analysis offers conclusive evidence to decode a biological system. Furthermore, animal models of optic nerve injury made it possible to gain insight into pathological mechanisms, therapeutic targets, and effective treatment of such injuries. Proteomics takes the proteome as the research object and studies protein changes in cells and tissues. At present, a variety of proteomic analysis methods have been widely used in the research of optic nerve injury diseases. This review summarizes the application of proteomic research in optic nerve injury diseases and animal models of optic nerve injury. Additionally, differentially expressed proteins are summarized and analyzed. Various optic nerve injuries, including those associated with different etiologies, are discussed along with their potential therapeutic targets and future directions.

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Sema3A Antibody BI-X Prevents Cell Permeability and Cytoskeletal Collapse in HRMECs and Increases Tip Cell Density in Mouse Oxygen-Induced Retinopathy

Cited by 9 publications

References 29 publications

BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies

BI-Y, an Neuropilin-1 Antagonist, Enhances Revascularization and Prevents Vascular Endothelial Growth Factor-A Induced Retinal Hyperpermeability in Rodent Models of Retinopathies

HORNBILL: a phase I/IIa trial examining the safety, tolerability and early response of BI 764524 in patients with diabetic retinopathy and diabetic macular ischaemia—rationale, study design and protocol

Application of Proteomics Analysis and Animal Models in Optic Nerve Injury Diseases

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