VEGFA Humanized and Transgenic Mice: Empowering Ophthalmology & Oncology Drug Development

How do we bridge the gap between preclinical research and breakthrough therapies for retinal diseases and cancer? VEGFA, a key regulator of blood vessel formation, has emerged as a pivotal target in treating conditions like age-related macular degeneration (AMD) and aggressive tumors. Yet, existing therapeutic strategies face significant challenges, underscoring the need for better tools in preclinical research.

Herein, Cyagen introduces VEGFA humanized & transgenic (TG) mouse models, engineered to mimic human VEGFA biology, providing an unparalleled platform for evaluating next-generation therapies. Whether you’re investigating novel anti-VEGF agents, combination cancer therapies, or multi-target strategies for retinal diseases, these models offer precision and versatility to accelerate your research.

Explore how B6-hVEGFA and hVEGFA-TG mice are transforming ophthalmology and oncology research—and discover why these models are essential for your next breakthrough. Read more to learn how they can redefine your approach to translational science.

Transformative Role of VEGFA in Angiogenesis and Disease Treatment

The discovery of vascular endothelial growth factor (VEGF) has profoundly transformed our understanding of the roles of angiogenesis (formation of new blood vessels) and vasculogenesis (the formation of the vascular system) in development and physiological homeostasis. Studies have shown that VEGF regulates angiogenesis and vascular permeability through multiple mechanisms. VEGF plays a pivotal role in tumor growth, metastasis, and the progression of retinal vascular diseases. Its central involvement in the pathological mechanisms of various cancers and blinding retinal diseases underscores VEGF’s therapeutic importance.^[1] 

Despite the advances made with VEGF-targeting therapies, such as anti-VEGF antibodies, challenges persist, driving the exploration of combination therapies and alternative angiogenesis-related targets. Reliable animal models are essential for preclinical drug testing, with humanized animal models offering great promise for advancing clinical translation.

Figure 1. The Research History of Vascular Endothelial Growth Factor (VEGF). ^[2]

1. The Role of VEGF in Retinal Diseases and Cancers

VEGFA has a dual role in promoting vascular homeostasis and pathological angiogenesis, critical pathophysiological processes that impact the development of retinal diseases and cancers.

Pathophysiology of VEGF in Retinal Diseases

In retinal diseases, VEGF contributes to maintaining vascular stability under hypoxic conditions but can lead to abnormal, leaky neovascularization under pathological circumstances, causing severe vision impairments like age-related macular degeneration (AMD) and diabetic retinopathy (DR). VEGF promotes vascular growth under hypoxic conditions to maintain tissue homeostasis; it is suppressed in hyperoxic environments, leading to capillary degeneration. Upon restoration of oxygen levels, VEGF expression is upregulated, triggering abnormal leaky neovascularization that can result in fibrosis, retinal detachment, and even blindness. ^[2] Excessive expression of VEGF in the eye can cause abnormal vascular proliferation and leakage, contributing to progressive AMD, DR, and corneal neovascularization, among other ocular diseases.

Role of VEGF in Cancerous Tumor Pathology & Oncology Research Applications

In oncology, VEGF secreted by tumor cells and the stroma drives angiogenesis to support tumor growth and elevated levels correlate with increased invasiveness and poor prognosis in malignant cancers. Currently, FDA-approved anti-angiogenic drugs primarily target the VEGF pathway. Anti-VEGF therapies, when combined with chemotherapy or immunotherapy, have become standard treatments for several malignancies.^[3] Similarly, these anti-VEGF therapies have achieved groundbreaking success in treating neovascular ocular diseases, such as AMD and ischemic retinal conditions.

Figure 2. The Role of VEGF in Tumors and Retinal Diseases.^[3]

2. Advancing VEGFA Research and Therapies

The VEGF family includes VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, and placental growth factor (PlGF), among which VEGFA is the primary regulator of angiogenesis and disease progression. VEGFA is mainly produced by tumor cells, immune cells, and damaged tissues. It activates downstream signaling pathways by binding to VEGFR1 and VEGFR2 receptors, which promotes endothelial cell proliferation, migration, and microvascular formation, thereby contributing to embryonic development, tissue repair, and inflammatory responses.^[3-4]

Retinal Disease Research Applications

In the retina, overexpression of VEGFA leads to the formation of retinal neovascularization, making VEGFA inhibition a key therapeutic approach for treating such diseases. In ophthalmology, VEGFA-targeted therapies require long-term administration and may lead to resistance. Therefore, multi-targeted approaches, such as combining with Ang-2 inhibitors, are being explored to reduce treatment burden and improve visual outcomes. ^[8-9]

Oncology & Cancer Research Applications

In tumors, VEGFA promotes tumor angiogenesis, supplying nutrients and oxygen to support tumor growth and metastasis.^[3-4] VEGFA-targeted therapies combined with cytotoxic agents, vascular-targeting drugs, or immune checkpoint inhibitors (such as PD-L1/PD-1 inhibitors) have shown enhanced antitumor efficacy and have great potential to become first-line treatments for various cancers.^[5-6]

Figure 3. Combining VEGFA Inhibitors with Other Antitumor Therapies Enhances Antitumor Efficacy. ^[2]

3. Cyagen’s Proprietary VEGFA Humanized Models and Disease Models

To advance the development of VEGFA-targeted therapies for retinal diseases and tumors, Cyagen has developed two key VEGFA-related models:

1. B6-hVEGFA mice (Product Code: C001555): Humanized mouse model with complete in situ humanization of the Vegfa gene locus;

2. hVEGFA-TG mice (Product Code: C001395): Transgenic mouse model with overexpression of the human VEGFA gene under a retina-specific promoter.

Below is the validation data for these humanized and transgenic mouse models of VEGFA developed for ophthalmic and oncologic research.

(1) B6-hVEGFA Mice

The B6-hVEGFA mice achieve complete humanization by replacing the mouse Vegfa gene with the human VEGFA gene, including the 3' UTR. Histological analyses show that B6-hVEGFA mice maintain normal retinal structure and photoreceptor function, validating the functionality of the humanized VEGFA gene.

Figure 4. B6-hVEGFA Mice Maintain Normal Retinal Structure and Photoreceptor Function.

(2) hVEGFA-TG Mice

The hVEGFA-TG transgenic mice (TG mice) express the human VEGFA gene CDS sequence under the control of a rod cell-specific promoter, while retaining the endogenous mouse Vegfa gene expression. This model spontaneously develops retinal and choroidal vascular abnormalities caused by VEGFA overexpression, supporting the preclinical in vivo efficacy evaluation of multiple candidate  anti-VEGFA drug molecules. Below is the efficacy evaluation data from evaluating the TG model with Aflibercept, a fusion protein that combines the Fc portion of human IgG with the ligand binding domains of the VEGRF1 and VEGRF2 receptors.

Figure 5. hVEGFA-TG Mice for Efficacy Validation of the VEGFA-Targeting Drug Aflibercept.

Why Choose Cyagen’s VEGFA Humanized Models?

• Precision and Versatility: The B6-hVEGFA model allows drug efficacy testing and can be crossed with immune checkpoint humanized mice (e.g., PD-1/PD-L1) to study combination therapies in oncology.
• Disease-Relevant Phenotypes: The hVEGFA-TG model provides a unique platform for researching retinal diseases and testing multi-target ophthalmic therapies involving VEGFA and Ang-2.

Both models cater to diverse research needs, complementing each other to advance drug discovery for cancer and retinal diseases.

Conclusion

Cyagen’s VEGFA humanized and transgenic mouse models are tailored for advancing translational research across ophthalmology and oncology. Our B6-hVEGFA mice (Product Code: C001555) are suitable for evaluating VEGFA-targeted therapies and can be bred with immune checkpoint humanized models (e.g., PD-1/PD-L1) to create multi-target humanized models for testing  combination treatments in oncology. Our hVEGFA-TG mice (Product Code: C001395), characterized by significant retinal and choroidal vascular lesions, are ideal for ophthalmic disease research and therapeutic evaluation. They can be crossed with Ang-2 humanized models to test multi-target therapies, such as VEGFA/Ang-2 drugs, for ophthalmic diseases. These complementary models cater to diverse research needs in retinal and cancer studies.

Cyagen also offers a wide array of inducible and genetically engineered mouse models for ophthalmology, oncology, and beyond. Our custom model generation capabilities include target-specific and whole-genome humanized models to deliver to the diverse needs of researchers in studying various diseases and developing therapies.

Contact us for more details or a free consultation to discuss your research needs.

Explore Cyagen’s Expertise in Disease Modeling

Cyagen offers an extensive portfolio of retinal disease models and tumor research models, including inducible, genetic, and fully humanized mouse models. These are tailored to meet the demands of translational research in multiple therapeutic areas.

Explore Cyagen’s Ophthalmic Disease Mouse Models:

Explore Cyagen’s Cancer Mouse Models:

References:

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[2]Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019 Mar 7;176(6):1248-1264.
[3]Pérez-Gutiérrez L, Ferrara N. Biology and therapeutic targeting of vascular endothelial growth factor A. Nat Rev Mol Cell Biol. 2023 Nov;24(11):816-834.
[4]Arcondéguy T, Lacazette E, Millevoi S, Prats H, Touriol C. VEGFA mRNA processing, stability and translation: a paradigm for intricate regulation of gene expression at the post-transcriptional level. Nucleic Acids Res. 2013 Sep;41(17):7997-8010.
[5]Sangro B, Sarobe P, Hervás-Stubbs S, Melero I. Advances in immunotherapy for hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2021 Aug;18(8):525-543.
[6]Lee WS, Yang H, Chon HJ, Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp Mol Med. 2020 Sep;52(9):1475-1485.
[7]Kuo HY, Khan KA, Kerbel RS. Antiangiogenic-immune-checkpoint inhibitor combinations: lessons from phase III clinical trials. Nat Rev Clin Oncol. 2024 Jun;21(6):468-482.
[8]Shirley M. Faricimab: First Approval. Drugs. 2022 May;82(7):825-830.
[9]Joussen AM, Ricci F, Paris LP, Korn C, Quezada-Ruiz C, Zarbin M. Angiopoietin/Tie2 signalling and its role in retinal and choroidal vascular diseases: a review of preclinical data. Eye (Lond). 2021 May;35(5):1305-1316.