Professor, Department of Cell Biology
Professor, Department of Ophthalmology
Assoc Director Oklahoma Center for Neuroscience
Director, DMEI/NEI Image Acquisition and Analysis Core Facility
B.S., Biology, Sienna College, Loudonville, New York
Ph.D., Cellular and Molecular Biology, State University New York at Buffalo, New York
Postdoctoral Training, Molecular Neurobiochemistry, Mental Retardation Research Center, UCLA School of Medicine Los Angeles, California
Association for Research in Vision and Ophthalmology (ARVO)
American Society of Biological Chemists & Molecular Biologists (ASBCMB)
American Association for the Advancement of Science (AAAS)
International Society of Experimental Eye Research (ISER)
Photoreceptor cells are incessantly bombarded with photons of light which, along with their high rate of oxygen metabolism, continuously exposes them to elevated levels of toxic reactive oxygen intermediates (ROI). Our data show that vacancy engineered, mixed valence state, cerium oxide nanoparticles (Nanoceria particles) scavenge ROI in vitro and prevent increases in the intracellular concentrations of ROI in primary cell cultures of rat retina. Most significantly, they prevent ROI induced blindness in rats. These data suggest the nanoceria particles may be effective in inhibiting the progression of ROI-induced cell death such as occurs in macular degeneration, retinitis pigmentosa, and other blinding diseases as well as the ROI-induced death of other cell types in diabetes, Alzheimer's Disease, atherosclerosis, stroke, etc. The use of nanoceria particles as direct therapy for multiple diseases represents a novel strategy and suggests they may represent a unique platform technology.
Many neurodegenerative diseases are known to occur and progress because of oxidative stress, the presence of reactive oxygen species (ROS) in excess of the cellular defensive capabilities. Age related macular degeneration (AMD), diabetic retinopathy (DR) and inherited retinal degeneration share ROS as a common node upstream of the blinding effects of these diseases. Knockout of the Vldlr gene results in a mouse that develops intraretinal and subretinal neovascular lesions within the first month of age and is an excellent model for a form of AMD called retinal angiomatous proliferation (RAP). Cerium oxide nanoparticles (nanoceria) catalytically scavenge ROS by mimicking the activities of superoxide dismutase and catalase. A single intravitreal injection of nanoceria into the Vldlr-/- eye was shown to inhibit: the rise in ROS in the Vldlr-/- retina, increases in vascular endothelial growth factor (VEGF) in the photoreceptor layer, and the formation of intraretinal and subretinal neovascular lesions. Of more therapeutic interest, injection of nanoceria into older mice (postnatal day 28) resulted in the regression of existing vascular lesions indicating that the pathologic neovessels require the continual production of excessive ROS. Our data demonstrate the unique ability of nanoceria to prevent downstream effects of oxidative stress in vivo and support their therapeutic potential for treatment of neurodegenerative diseases such as AMD and DR.
Methods used - For live animal longitudinal studies on the same animal over time, electroretinography (ERG) for retinal function; optical coherence tomography (OCT) for edema and retinal degeneration; fundoscopy for imaging retinal/choroidal vasculature and leakage; Visual Optomotor Task Assessment: The OptoMotry System for assessing rodent visual acuity and contrast sensitivity. These projects may also involve isolation of plasmid DNA, cloning, subcloning, restriction enzymes, Southern's, Northern's, Yeast two hybrid screen, Western's, electrophoretic mobility shift assays, the polymerase chain reaction(PCR), RTPCR, 1-D and 2-D gel electrophoresis, protein purification, transfections, primary cell culture of mammalian neurons, immunocytochemistry, in vivo transfection, siRNA, fluorescence microscopy, confocal microscopy, in situ hybridization, preparative electrophoresis and the detection and functional evaluation of Nanoceria particles.
Chen, J., Patil, S., Seal, S., and McGinnis, J.F. Rare Earth Nanoparticles Prevent Retinal Degeneration Induced by Intracellular Peroxides. Nature Nanotechnology 1:142-150, 2006.
Chen, J., Wu, M., Sezate, S.A., Matsumoto, H., Ramsey, M., McGinnis, J.F. Interaction of Glyceraldehyde-3-Phosphate Dehydrogenase in the Light-Induced Rod Alpha-Transducin Translocation. J Neurochem 104:1280-1292, 2008.
Zhou, X., Wong, L.L., Karakoti,A.S., Seal,S. and McGinnis, J.F. (2011) Nanoceria Inhibit the Development and Promote the Regression of Pathologic Retinal Neovascularization in the Vldlr knockout mouse. PLoS. ONE 2011, 6, e16733, doi:10.1371/journal.pone.0016733 [doi].
Kong, L., Cai, X., Zhou, X., Wong, L.L., Karakoti, A.S., Seal, S. and McGinnis, J.F. (2011) Nanoceria Extend Photoreceptor Cell Lifespan in Tubby Mice by Modulation of Apoptosis/Survival Signaling Pathways. Neurobiol. Dis. (2011), doi: 10.1016/j.nbd.2011.03.004.
Cai X, Sezate SA, Seal S, McGinnis JF. Sustained protection against photoreceptor degeneration in tubby mice by intravitreal injection of nanoceria. Biomaterials. 2012 Dec; 33(34):8771-81. doi: 10.1016/j.biomaterials.2012.08.030. Epub 2012 Sep
Sun,X., Haley,J., Bulgakovoleg,O.V., Cai,X., McGinnis,J. & Li,T. (2012). Tubby is required for trafficking g protein-coupled receptors to neuronal cilia. Cilia., 1, 21. PMID:23351594
Wong,L.L., Hirst,S.M., Pye,Q.N., Reilly,C.M., Seal,S. & McGinnis,J.F. (2013). Catalytic nanoceria are preferentially retained in the rat retina and are not cytotoxic after intravitreal injection. PLoS.ONE., 8, e58431.
Svetlana V. Kyosseva, Lijuan Chen, Sudipta Seal, James J. McGinnis. (2013). Nanoceria inhibit expression of genes associated with inflammation and angiogenesis in the retina of Vldlr null mice. Exp Eye Res 116, 63–74, 2013 http://dx.doi.org/10.1016/j.exer.2013.08.003
Das,S., Dowding,J.M., Klump,K.E., McGinnis,J.F., Self,W. & Seal,S. (2013 ). Cerium oxide nanoparticles: applications and prospects in nanomedicine. Nanomedicine.(Lond), 8, 1483-1508.
Cai X, Seal S, McGinnis JF. Sustained inhibition of neovascularization in vldlr_/_ mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-kB pathway (2013). In press October 2013, Biomaterials.
Dean A. McGee Eye Institute
Department of Ophthalmology
608 Stanton L. Young, Blvd.
Oklahoma City, OK 73126-0901
Phone: (405) 271-3692
Fax: (405) 271-3721