Prolonged Inhibition of Pathologic Neovascularization by Catalytic Antioxidants

Summary

Principal Investigator: JAMES FRANCIS MCGINNIS
Abstract: DESCRIPTION (provided by applicant): In some forms of Diabetic Retinopathy (DR) and Macular Degeneration (AMD), blindness results from the pathologic development of new blood vessels which are incomplete, weak and porous. The progression of these neovascular diseases is thought to occur through the production of toxic molecules, Reactive Oxygen Species (ROS). There are no long term successful therapies for such diseases which have devastating effects on patients and cost the USA over $50 billion/yr. Our long term goal is to develop a therapeutic treatment to protect the health and function of retinal cells and thereby prolong vision and improve the quality of life for patients with DR or AMD. Because the excessive rise in ROS occurs "upstream" of most other retinal pathologies, it represents a common node which can be targeted by antioxidants and other molecules which increase the expression of "Phase II" antioxidant enzymes. Our published and preliminary data show that cerium oxide nanoparticles, which catalytically destroy ROS, can prevent development of pathologic choroidal and retinal neovascular lesions and cause the regression of existing pathologic neovessels in the Very Low Density Lipoprotein Receptor null retina by modulating the expression of many retinal genes including Vascular Endothelial Growth Factor (VEGF). Our central hypothesis is that cerium oxide nanoparticles, because of their catalytic antioxidant activity and long term retention in the retina, will continuously scavenge ROS and inhibit pathologic neovascularization over prolonged times -up to 12 months. Specific aim 1 will determine duration of nanoceria in the retina and the extent to which they retain activity against neovascularization. Inductively coupled plasma mass spectrometry will quantitate cerium at the parts per billion levels. Fundoscopy, electroretinography and optical coherence tomography will be used for longitudinal studies on the same animal to evaluate neovascularization, retinal function and thickness of the outer nuclear layer. Nanoceria effects on specific genes involved in oxidative stress, inflammation and neovascularization will be analyzed using confocal microscopy, Western blots and PCR arrays. Specific Aim 2 will demonstrate that nanoceria provide protection to the retina by reducing the effects of oxidative stress on photoreceptors and Retinal Pigment Epithelial (RPE) cells. Gene activity, proteins and structures indicative of photoreceptor- and/or RPE- oxidative stress will be evaluated. Specific Aim 3 will test the hypothesis that the combinatorial use of nanoceria and sulforaphane, an inducer of Phase II antioxidant enzymes, will result in an additive or synergistic effects in the Vldlr retina. Expected outcomes - the work proposed is expected to demonstrate the longevity, potency and mechanisms by which nanoceria inhibit pathologic neovascularization in the retina. The results are expected to have an important positive impact because the demonstration of the long term effectiveness of the nanoceria will most likely support their therapeutic use and changes in activity of identified genes should provide additional targets important for treating DR, AMD and other diseases which involve oxidative stress.
Funding Period: 2012-02-01 - 2016-01-31
more information: NIH RePORT

Top Publications

  1. pmc Catalytic nanoceria are preferentially retained in the rat retina and are not cytotoxic after intravitreal injection
    Lily L Wong
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, College of Medicine, and Dean McGee Eye Institute, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 8:e58431. 2013
  2. pmc Nanoceria inhibit expression of genes associated with inflammation and angiogenesis in the retina of Vldlr null mice
    Svetlana V Kyosseva
    Department of Ophthalmology Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Electronic address
    Exp Eye Res 116:63-74. 2013
  3. ncbi Cerium oxide nanoparticles: applications and prospects in nanomedicine
    Soumen Das
    Advanced Materials Processing Analysis Center, NanoScience Technology Center, University of Central Florida, Orlando, FL, USA
    Nanomedicine (Lond) 8:1483-508. 2013
  4. pmc Sustained inhibition of neovascularization in vldlr-/- mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-κB pathway
    Xue Cai
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Electronic address
    Biomaterials 35:249-58. 2014
  5. ncbi Nanoceria and thioredoxin regulate a common antioxidative gene network in tubby mice
    Xue Cai
    Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L Young Blvd, 73104, Oklahoma City, OK, USA
    Adv Exp Med Biol 801:829-36. 2014
  6. pmc Understanding the adsorption interface of polyelectrolyte coating on redox active nanoparticles using soft particle electrokinetics and its biological activity
    Shashank Saraf
    Advanced Materials Processing and Analysis Center AMPAC, Materials Science Engineering MSE, University of Central Florida, 4000 Central Florida Boulevard, Orlando, Florida 32816, United States
    ACS Appl Mater Interfaces 6:5472-82. 2014

Detail Information

Publications6

  1. pmc Catalytic nanoceria are preferentially retained in the rat retina and are not cytotoxic after intravitreal injection
    Lily L Wong
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, College of Medicine, and Dean McGee Eye Institute, Oklahoma City, Oklahoma, United States of America
    PLoS ONE 8:e58431. 2013
    ....
  2. pmc Nanoceria inhibit expression of genes associated with inflammation and angiogenesis in the retina of Vldlr null mice
    Svetlana V Kyosseva
    Department of Ophthalmology Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Electronic address
    Exp Eye Res 116:63-74. 2013
    ..These data suggest that nanoceria may represent a novel therapeutic strategy to treat AMD, RAP, and other neurodegenerative diseases. ..
  3. ncbi Cerium oxide nanoparticles: applications and prospects in nanomedicine
    Soumen Das
    Advanced Materials Processing Analysis Center, NanoScience Technology Center, University of Central Florida, Orlando, FL, USA
    Nanomedicine (Lond) 8:1483-508. 2013
    ..CNPs are well tolerated in both in vitro and in vivo biological models, which makes CNPs well suited for applications in nanobiology and regenerative medicine. ..
  4. pmc Sustained inhibition of neovascularization in vldlr-/- mice following intravitreal injection of cerium oxide nanoparticles and the role of the ASK1-P38/JNK-NF-κB pathway
    Xue Cai
    Department of Ophthalmology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA Electronic address
    Biomaterials 35:249-58. 2014
    ....
  5. ncbi Nanoceria and thioredoxin regulate a common antioxidative gene network in tubby mice
    Xue Cai
    Department of Ophthalmology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L Young Blvd, 73104, Oklahoma City, OK, USA
    Adv Exp Med Biol 801:829-36. 2014
    ..Our data demonstrate that nanoceria and Trx regulate the same group of genes associated with antioxidative stress and antioxidant defense. ..
  6. pmc Understanding the adsorption interface of polyelectrolyte coating on redox active nanoparticles using soft particle electrokinetics and its biological activity
    Shashank Saraf
    Advanced Materials Processing and Analysis Center AMPAC, Materials Science Engineering MSE, University of Central Florida, 4000 Central Florida Boulevard, Orlando, Florida 32816, United States
    ACS Appl Mater Interfaces 6:5472-82. 2014
    ..This indicates that the catalase activity is also affected by the structure of the coating layer. ..

Research Grants30

  1. Investigation of autoimmune anti-retinal antibodies in diabetes
    John R Heckenlively; Fiscal Year: 2013
    ..Specific immunoreactive bands will be processed for mass spectrometry, and candidate proteins will be identified and the correct ones confirmed. ..
  2. Role of Caveolin-1 in the Maintenance of Blood-retinal Barrier Integrity
    Michael H Elliott; Fiscal Year: 2013
    ..The final aim will focus on the role that dysregulation of the Na/K-ATPase plays and how Cav-1 regulates ATPase activity. ..
  3. Safety and Toxicology Studies of CLT-005 as a Therapeutic for Diabetic Macular Ed
    RAFAL A FARJO; Fiscal Year: 2013
    ..Although we intend to seek an initial indication for DME, it is likely that CLT-005 will also confer a significant therapeutic benefit to patients suffering from Diabetic Retinopathy and Age-Related Macular Degeneration. ..