Dataset Information

Anti-Angiogenic and Anti-Scarring Dual Action of an Anti-Fibroblast Growth Factor 2 Aptamer in Animal Models of Retinal Disease.

ABSTRACT: Currently approved therapies for age-related macular degeneration (AMD) are inhibitors against vascular endothelial growth factor (VEGF), which is a major contributor to the pathogenesis of neovascular AMD (nAMD). Intravitreal injections of anti-VEGF drugs have shown dramatic visual benefits for AMD patients. However, a significant portion of AMD patients exhibit an incomplete response to therapy and, over the extended management course, can lose vision, with the formation of submacular fibrosis as one risk factor. We investigated a novel target for AMD treatments, fibroblast growth factor 2 (FGF2), which has been implicated in the pathophysiology of both angiogenesis and fibrosis in a variety of tissue and organ systems. The anti-FGF2 aptamer, RBM-007, was examined for treatment of nAMD in animal models. In in vivo studies conducted in mice and rats, RBM-007 was able to inhibit FGF2-induced angiogenesis, laser-induced choroidal neovascularization (CNV), and CNV with fibrosis. Pharmacokinetic studies of RBM-007 in the rabbit vitreous revealed high and relatively long-lasting profiles that are superior to other approved anti-VEGF drugs. The anti-angiogenic and anti-scarring dual action of RBM-007 holds promise as an additive or alternative therapy to anti-VEGF treatments for nAMD.

SUBMITTER: Matsuda Y

PROVIDER: S-EPMC6716068 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Publications

Anti-Angiogenic and Anti-Scarring Dual Action of an Anti-Fibroblast Growth Factor 2 Aptamer in Animal Models of Retinal Disease.

Matsuda Yusaku Y Nonaka Yosuke Y Futakawa Satoshi S Imai Hirotaka H Akita Kazumasa K Nishihata Toshiaki T Fujiwara Masatoshi M Ali Yusuf Y Bhisitkul Robert B RB Nakamura Yoshikazu Y

Molecular therapy. Nucleic acids 20190801

Currently approved therapies for age-related macular degeneration (AMD) are inhibitors against vascular endothelial growth factor (VEGF), which is a major contributor to the pathogenesis of neovascular AMD (nAMD). Intravitreal injections of anti-VEGF drugs have shown dramatic visual benefits for AMD patients. However, a significant portion of AMD patients exhibit an incomplete response to therapy and, over the extended management course, can lose vision, with the formation of submacular fibrosis ...[more]

PMID: 31454678

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Project description:IntroductionA reproducible, standardised model for cutaneous scar tissue to assess therapeutics is crucial to the progress of the field. A systematic review was performed to critically evaluate scarring models in both animal and human research.MethodAll studies in which cutaneous scars are modelling in animals or humans were included. Models that were focused on the wound healing process or those in humans with scars from an existing injury were excluded. Ovid Medline® was searched on 25 February 2019 to perform two near identical searches; one aimed at animals and the other aimed at humans. Two reviewers independently screened the titles and abstracts for study selection. Full texts of potentially suitable studies were then obtained for analysis.ResultsThe animal kingdom search yielded 818 results, of which 71 were included in the review. Animals utilised included rabbits, mice, pigs, dogs and primates. Methods used for creating scar tissue included sharp excision, dermatome injury, thermal injury and injection of fibrotic substances. The search for scar assessment in humans yielded 287 results, of which 9 met the inclusion criteria. In all human studies, sharp incision was used to create scar tissue. Some studies focused on patients before or after elective surgery, including bilateral breast reduction, knee replacement or midline sternotomy.DiscussionThe rabbit ear scar model was the most popular tool for scar research, although pigs produce scar tissue which most closely resembles that of humans. Immunodeficient mouse models allow for in vivo engraftment and study of human scar tissue, however, there are limitations relating to the systemic response to these xenografts. Factors that determine the use of animals include cost of housing requirements, genetic traceability, and ethical concerns. In humans, surgical patients are often studied for scarring responses and outcomes, but reproducibility and patient factors that impact healing can limit interpretation. Human tissue use in vitro may serve as a good basis to rapidly screen and assess treatments prior to clinical use, with the advantage of reduced cost and setup requirements.

Project description:Background: Pathological angiogenesis is the hallmark of many vision-threatening diseases. Anti-VEGF is a primary treatment with substantial beneficial effects. However, such agents require frequent intravitreal injections. Our previous work established a method for effectively modifying exosomes (EXOs) for loading therapeutic peptides. Here, we used this system to load the anti-angiogenic peptide KV11, aiming to establish an EXO-based therapy strategy to suppress neovascularization in the retina. Methods: Using an anchoring peptide, CP05, we linked KV11 to endothelial cell (EC) derived EXOs, yielding EXOKV11. We tested the delivery efficiency of EXOKV11 via two commonly used ocular injection methods: retro-orbital injection and intravitreal injection. Deploying an oxygen-induced retinopathy (OIR) model and a VEGF injection model, we tested the effects of EXOKV11 on neovascular formation, EC proliferation, and vascular permeability. In vitro experiments were used to test the mechanism and to analyze the effects of EXOKV11 on EC proliferation, migration, and sprouting. Results: By using the EXO loading system, KV11 was more efficiently delivered to the blood vessels of the mouse retina via retro-orbital injection. In both OIR model and VEGF injection model, EXOKV11 was more effective than KV11 alone in inhibiting neovascularization and vessel leakage. The therapeutic effect of retro-orbital injection of EXOKV11 was comparable to the intravitreal injection of VEGF-trap. Mechanistically, KV11 alone inhibited VEGF-downstream signaling, while EXOKV11 showed a stronger effect. Conclusions: We used EXOs as a carrier for intraocular delivery of KV11. We showed that KV11 itself has an anti-angiogenic effect through retro-orbital injection, but that this effect was greatly enhanced when delivered with EXOs. Thus, this system has the potential to treat proliferative retinopathy via retro-orbital injection which is a less invasive manner compared with intravitreal injection.

Dataset Information

Anti-Angiogenic and Anti-Scarring Dual Action of an Anti-Fibroblast Growth Factor 2 Aptamer in Animal Models of Retinal Disease.

Publications

Anti-Angiogenic and Anti-Scarring Dual Action of an Anti-Fibroblast Growth Factor 2 Aptamer in Animal Models of Retinal Disease.

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