Age-related macular degeneration (AMD) is characterized by progressively decreased central vision and visual acuity and remains a leading cause of vision loss and blindness in aged Americans. Currently, the standard of care for AMD is intravitreal vascular endothelial growth factor (VEGF) inhibitors. Clinical studies have demonstrated that anti-VEGF drugs can slow or reverse the progression of wet-AMD. However, these therapies are not always effective in all patients. AMD is a multi-factorial disease involving numerous pathogenic factors, such as VEGF, platelet-derived growth factor (PDGF), intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-alpha (TNF-¿), cyclooxygenase-2 (Cox-2), connective tissue growth factor (CTGF), and fibronectin (FN), that contribute to angiogenesis, inflammation, fibrosis and oxidative stress in AMD. Thus, targeting a VEGF or VEGF receptors alone may not benefit all cases of AMD, and there is a great demand for developing more effective therapeutic options with multiple targets or new targets. Accumulated evidence has demonstrated that the inappropriate activation of Wnt pathway plays an important role in AMD. The Wnt pathway is involved in multiple pathological processes of AMD, including the formation of new blood vessels, vascular leakage, inflammation, fibrosis and oxidative stress, as it regulates many Wnt target genes which are known pathogenic factors in AMD, e.g. VEGF, PDGF, ICAM-1, TNF-¿, Cox- 2, CTGF and FN. Since Wnt pathway inhibitors can simultaneously down-regulate multiple pathogenic factors, they should be more superior to anti-VEGF therapeutics. Therefore, the Wnt pathway has become an attractive target of new drugs for the treatment of AMD. Through synthesizing and screening over 100 curcumin derivatives, CLT-010-71S, has been identified as a leading small molecule compound for blocking Wnt signaling. Preliminary data showed that the compound attenuated the Wnt pathway activation as it blocked the phosphorylation of low-density lipoprotein receptor- related protein 6 (LRP6), an essential step in Wnt pathway activation, and enhanced the phosphorylation of ¿- catenin to lead to ¿-catenin degradation. The compound also inhibited Wnt3a-induced expression of Wnt target genes including VEGF, ICAM-1, CTGF and FN. Moreover, CLT-010-71S specifically inhibited the growth of retinal vascular endothelial cells. These findings indicate that CLT-010-71S is a promising drug candidate for AMD. As an increasingly used genetic model of wet-AMD, very low-density lipoprotein receptor gene knock-out (Vldlr-/-) mouse has been widely used for new ocular drug discovery. This SBIR Phase I project will serve as a proof-of-concept study to assess the in vivo efficacies of CLT-010-71S on Wnt signaling activation, Wnt target gene expression, inflammation and vascular leakage in Vldlr-/- mice. The program includes two specific aims: Aim 1 will determine the effects of CLT-010-71S on the Wnt pathway activation and Wnt target gene expression. Aim 2 will evaluate the efficacies of CLT-010-71S on inflammation and vascular leakage. The proposed studies will lay a solid groundwork for future preclinical studies of CLT-010-71S in Phase II. The project has potential to develop a treatment with a novel target other than VEGF to cure AMD. This new treatment could be applied together with anti-VEGF agents or as an alternative.
Public Health Relevance Statement: Public Health Relevance: Age-related macular degeneration (AMD) remains a leading cause of vision loss and blindness in aged Americans. Current therapies have limited benefit and are not always effective in all patients with AMD. Thus, there is a great demand for developing more effective therapeutic options to improve the treatment of AMD. The project will develop a treatment with a novel target other than vascular endothelial growth factor (VEGF) to cure AMD.
Project Terms: Age related macular degeneration; aged; American; angiogenesis; Animals; Attenuated; Biological Assay; Blindness; Blood Vessels; Blood-Retinal Barrier; Characteristics; Choroidal Neovascularization; Clinical Research; Concanavalin A; connective tissue growth factor; Cultured Cells; Curcumin; cyclooxygenase 2; Data; Development; Disease; Dose; drug candidate; Drug Delivery Systems; drug discovery; Drug Formulations; Drug Kinetics; Extravasation; Fibronectins; Fibrosis; Fluorescein; Future; Gene Expression; Gene Targeting; Genetic Models; Growth; improved; in vivo; Inflammation; inhibitor/antagonist; Intercellular adhesion molecule 1; intravitreal injection; Isothiocyanates; Knockout Mice; Label; LDL-Receptor Related Protein 1; Lead; Leukocytes; Leukostasis; lipoprotein receptor-related protein 6; Measures; neovascularization; novel; Nuclear Translocation; Oxidative Stress; Pathologic Processes; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phase; Phosphorylation; Platelet-Derived Growth Factor; Play; preclinical study; programs; Proteins; public health relevance; Rattus; Receptor Gene; Recombinants; Retinal; Role; screening; Signal Transduction; Small Business Innovation Research Grant; small molecule; Solid; standard of care; Synthesis Chemistry; Therapeutic; TNF gene; Toxicology; Tumor Necrosis Factor-alpha; Vascular Endothelial Cell; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; vascular inflammation; Vision; Visual Acuity; VLDL recepto
