A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy

Chidiac, Rony; Abedin, Md. Joynal; MacLeod, Graham; Yang, Andy; Thibeault, Pierre E.; Blazer, Levi L.; Adams, Jarrett; Zhang, Lingling; Roehrich, Heidi; Jo, Ha-neul; Seshagiri, Somasekar; Sidhu, Sachdev S.; Junge, Harald J.; Angers, Stéphane

doi:10.15252/emmm.202113977

Cited by 42 publications

(51 citation statements)

References 36 publications

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“…Activation of FZD4 signaling induces protein expressions for vascular barrier functions (e.g., claudin-5 [Cldn5], zonula occludens-1 [Zo-1], major facilitator superfamily domain containing 2 [Mfsd2]) and reduces the expression of plasmalemma vesicle-associated protein (Plvap), a marker of immature or leaky retinal vessels, 23 – 25 which restrains vascular leakage. Additionally, it has been shown that intravitreal injection of Norrin can restore the BRB properties to some degree in streptozotocin-induced diabetic rats 26 and that stabilizing β-catenin in the choriocapillaris switches its permeable nature to a BRB-like state.…”

Section: Introductionmentioning

confidence: 99%

SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy

Nguyen¹,

Chen²,

Vuppalapaty³

et al. 2022

Trans. Vis. Sci. Tech.

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Purpose There remains a high unmet need for therapies with new mechanisms of action to achieve reperfusion of ischemic retina in diabetic retinopathy. We examined whether a novel frizzled class receptor 4 (FZD4) agonist could promote regeneration of functional blood vessels in animal models of retinopathy. Methods We developed a novel Norrin mimetic (SZN-413-p) targeting FZD4 and low-density lipoprotein receptor-related protein 5 (LRP5) and examined its effect on retinal and brain endothelial cells in vitro. SZN-413-p was subsequently humanized, resulting in the therapeutic candidate SZN-413, and was examined in animal models of retinopathy. In an oxygen-induced retinopathy mouse model, avascular and neovascularization areas were measured. Furthermore, in a vascular endothelial growth factor (VEGF)-induced retinal vascular leakage rabbit model, the impact on vascular leakage by SZN-413 was examined by measuring fluorescein leakage. Results SZN-413-p induced Wnt/β-catenin signaling and upregulated blood–brain barrier/blood–retina barrier gene expressions in endothelial cells. In the oxygen-induced retinopathy mouse model, SZN-413-p and SZN-413 significantly reduced the neovascularization area size ( P < 0.001) to a level comparable to, or better than the positive control aflibercept. Both agonists also showed a reduction in avascular area size compared to vehicle ( P < 0.001) and aflibercept groups ( P < 0.05 and P < 0.01 for SZN-413-p and SZN-413, respectively). In the VEGF-induced retinal vascular leakage rabbit model, SZN-413 reduced retinal vascular leakage by ∼80%, compared to the vehicle-treated group ( P < 0.01). Conclusions Reduction of neovascular tufts and avascular areas and of VEGF-driven retinal vascular leakage suggests that SZN-413 can simultaneously address retinal non-perfusion and vascular leakage. Translational Relevance FZD4 signaling modulation by SZN-413 is a novel mechanism of action that can offer a new therapeutic strategy for diabetic retinopathy.

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Section: Introductionmentioning

confidence: 99%

SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy

Nguyen¹,

Chen²,

Vuppalapaty³

et al. 2022

Trans. Vis. Sci. Tech.

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“…They showed that endocytosis of FZD4 in Norrin/Fzd4/β-catenin signaling axis is an important mechanistic step to maintaining iBRB and low PLVAP levels [ 20 ]. A more recent study showed that an FZD4/LRP5 agonist fully or partially restored transcellular iBRB function (associated with suppressed PLVAP levels and extravasated FITC dextran) with or without the amelioration of aberrant angiogenesis, respectively, in young (P20) or adult (3-month-old) Tspan12 −/− Wnt-deficient mouse retinas [ 134 ], further supporting the role of PLVAP in iBRB.…”

Section: Wnt Signaling and Ibrb Maintenancementioning

confidence: 88%

“…Methods to target Wnt signaling have been explored as potential therapeutics to restore iBRB in both development and diseases. Recently, Chidiac and colleagues [ 134 ] developed a bispecific antibody (F4L5.13) to trigger FZD4 and LRP5 proximity such that β-catenin signaling is activated. The stimulation of cultured ECs with the antibody caused the reversal of VEGF-induced permeability, partially by promoting surface expression of the junctional proteins ZO-1, claudin3, and claudin5.…”

Section: Wnt Signaling and Ibrb Maintenancementioning

confidence: 99%

“…The stimulation of cultured ECs with the antibody caused the reversal of VEGF-induced permeability, partially by promoting surface expression of the junctional proteins ZO-1, claudin3, and claudin5. Moreover, the treatment of Tspan12 −/− Wnt-deficient mice with the antibody (from P5 to P20) restored retinal angiogenesis and barrier function (claudin5) [ 134 ]. Similarly, the injection of Norrin in diabetic rats restored BRB integrity after additional VEGF-induced permeability by inducing claudin5 and the tight junction complex [ 135 ], suggesting the possibility of targeting Wnt ligands, receptors, or downstream pathways as therapeutics to restore iBRB integrity in the developmental stage, or by countering hyperpermeability induced by other factors such as VEGF and potentially TGFβ in pathological conditions.…”

Section: Wnt Signaling and Ibrb Maintenancementioning

confidence: 99%

“…As a result, Arima and colleagues [ 178 ] showed that in diabetic mice, resistance to anti-VEGFs in DME is partly due to inflammation, which activates rho-associated coiled-coil containing kinase 2 to redistribute claudin5. While VEGF is a known Wnt target gene, recent studies on Wnt activation to restore hyperpermeability induced by VEGF provide potential clues on mitigating Wnt signaling to counter iBRB breakdown induced by abnormally high levels of VEGF [ 134 , 135 ]. Yet, much more work is needed to determine in detail the correct time window and level of control needed to titrate Wnt signaling to achieve physiological iBRB control.…”

Section: Interplay Of Wnt/β-catenin Signaling With Other Mechanisms Underpinning Ibrb Maintenance and Breakdown In Eye Diseasesmentioning

confidence: 99%

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Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

Yemanyi

Bora

Blomfield

et al. 2021

IJMS

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The retina is a light-sensing ocular tissue that sends information to the brain to enable vision. The blood–retinal barrier (BRB) contributes to maintaining homeostasis in the retinal microenvironment by selectively regulating flux of molecules between systemic circulation and the retina. Maintaining such physiological balance is fundamental to visual function by facilitating the delivery of nutrients and oxygen and for protection from blood-borne toxins. The inner BRB (iBRB), composed mostly of inner retinal vasculature, controls substance exchange mainly via transportation processes between (paracellular) and through (transcellular) the retinal microvascular endothelium. Disruption of iBRB, characterized by retinal edema, is observed in many eye diseases and disturbs the physiological quiescence in the retina’s extracellular space, resulting in vision loss. Consequently, understanding the mechanisms of iBRB formation, maintenance, and breakdown is pivotal to discovering potential targets to restore function to compromised physiological barriers. These unraveled targets can also inform potential drug delivery strategies across the BRB and the blood–brain barrier into retinas and brain tissues, respectively. This review summarizes mechanistic insights into the development and maintenance of iBRB in health and disease, with a specific focus on the Wnt signaling pathway and its regulatory role in both paracellular and transcellular transport across the retinal vascular endothelium.

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The emerging understanding of Frizzled receptors

Zheng,

Sheng

2024

FEBS Letters

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The Wnt signaling pathway is a huge network governing development and homeostasis, dysregulation of which is associated with a myriad of human diseases. The Frizzled receptor (FZD) family comprises receptors for Wnt ligands, which indispensably mediate Wnt signaling jointly with a variety of co‐receptors. Studies of FZDs have revealed that 10 FZD subtypes play diverse roles in physiological processes. At the same time, dysregulation of FZDs is also responsible for various diseases, in particular human cancers. Enormous attention has been paid to the molecular understanding and targeted therapy of FZDs in the past decade. In this review, we summarize the latest research on FZD structure, function, regulation and targeted therapy, providing a basis for guiding future research in this field.

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A Norrin/Wnt surrogate antibody stimulates endothelial cell barrier function and rescues retinopathy

Cited by 42 publications

References 36 publications

SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy

SZN-413, a FZD4 Agonist, as a Potential Novel Therapeutic for the Treatment of Diabetic Retinopathy

Wnt Signaling in Inner Blood–Retinal Barrier Maintenance

The emerging understanding of Frizzled receptors

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