An interdisciplinary consortium of investigators from the Departments of Ophthalmology and Pediatrics at the University of Wisconsin in collaboration with the Northwestern University Chemistry of Life Processes Institute, Biomedical Engineering, Urology, and Pediatrics, and the University of Nebraska Center for Drug Delivery and Nanomedicine, proposes to increase the pace at which basic science discoveries on disease mechanisms can be translated into therapies for exudative age-related macular degeneration (AMD), a stated goal of the R24 National Eye Institute Translational Research Program on Therapy for Visual Disorders. This scientific partnership will employ its diverse scientific expertise to characterize and test potential therapies for exudative AMD in animal models by using a combination of cutting-edge physiological, chemical, analytical and imaging approaches. By screening novel peptides derived from endogenous inhibitors of angiogenesis for their ability to prevent neovascularization in animal models that mimic AMD, we will accelerate drug development before testing in humans. Improving drug delivery to the eye as an integral part of these experiments will also be a high priority. Specific goals of this project are to: (1) determin whether the peptide mechanisms of action in the eye are through their mimicry of these natural inhibitors;(2) Produce and identify optimal new derivatives of benchmark peptides best suited to intravitreal treatment of AMD, where these are ranked by efficacy in CNV models, individually and in combination;(3) Select and tested the most active peptide(s) and their most slowly cleared formulations for efficacy in AMD models. The best candidate(s) will undergo GLP production and then safety testing, including retinal safety to select a suitable new peptide-based entity for clinical development;and (4) Establish preclinical basis for ultimate human treatment protocol for this entity through animal models of retinal disease examined via state-of-the art in vivo retinal imaging and histopathological analysis. Ultimately, the experimental result of these interrelated aims will guide us in developing more successful therapies for those afflicted by currently incurable blinding diseases with a neovascular component.

Public Health Relevance

Identification of effective compounds that can arrest the disease state with minimal systemic side effects, and alleviate the necessity of repeated intravitreal delivery is vital for effective treatment of AMD. Utilizing a mechanistically relevant model of AMD, we have demonstrated rapid screening to test a broad set of novel peptide molecules. This proposal offers a compelling opportunity to attack exudative AMD.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Resource-Related Research Projects (R24)
Project #
1R24EY022883-01
Application #
8415053
Study Section
Special Emphasis Panel (ZEY1-VSN (05))
Program Officer
Agarwal, Neeraj
Project Start
2013-03-01
Project End
2018-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
1
Fiscal Year
2013
Total Cost
$1,243,462
Indirect Cost
$172,008
Name
University of Wisconsin Madison
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Farnoodian, Mitra; Sorenson, Christine M; Sheibani, Nader (2018) Negative Regulators of Angiogenesis, Ocular Vascular Homeostasis, and Pathogenesis and Treatment of Exudative AMD. J Ophthalmic Vis Res 13:470-486
Saghiri, Mohammad Ali; Asatourian, Armen; Nguyen, Eric H et al. (2018) Hydrogel Arrays and Choroidal Neovascularization Models for Evaluation of Angiogenic Activity of Vital Pulp Therapy Biomaterials. J Endod 44:773-779
Melgar-Asensio, Ignacio; Kandela, Irawati; Aird, Fraser et al. (2018) Extended Intravitreal Rabbit Eye Residence of Nanoparticles Conjugated With Cationic Arginine Peptides for Intraocular Drug Delivery: In Vivo Imaging. Invest Ophthalmol Vis Sci 59:4071-4081
Gurel, Zafer; Sheibani, Nader (2018) O-Linked ?-N-acetylglucosamine (O-GlcNAc) modification: a new pathway to decode pathogenesis of diabetic retinopathy. Clin Sci (Lond) 132:185-198
Saghiri, Mohammad Ali; Asatourian, Armen; Sheibani, Nader (2018) Angiogenesis and the prevention of alveolar osteitis: a review study. J Korean Assoc Oral Maxillofac Surg 44:93-102
Saghiri, Mohammad Ali; Asatourian, Armen; Sorenson, Christine M et al. (2018) Mice dental pulp and periodontal ligament endothelial cells exhibit different proangiogenic properties. Tissue Cell 50:31-36
Urban, Ben Ewell; Xiao, Lei; Chen, Siyu et al. (2018) In Vivo Superresolution Imaging of Neuronal Structure in the Mouse Brain. IEEE Trans Biomed Eng 65:232-238
Zaitoun, Ismail S; Cikla, Ulas; Zafer, Dila et al. (2018) Attenuation of Retinal Vascular Development in Neonatal Mice Subjected to Hypoxic-Ischemic Encephalopathy. Sci Rep 8:9166
Liu, Qi; Chen, Siyu; Soetikno, Brian et al. (2018) Monitoring Acute Stroke in Mouse Model Using Laser Speckle Imaging-Guided Visible-Light Optical Coherence Tomography. IEEE Trans Biomed Eng 65:2136-2142
Farnoodian, Mitra; Wang, Shoujian; Dietz, Joel et al. (2017) Negative regulators of angiogenesis: important targets for treatment of exudative AMD. Clin Sci (Lond) 131:1763-1780

Showing the most recent 10 out of 128 publications