title: Oral Monomethyl Fumarate Therapy Ameliorates Retinopathy in a Humanized Mouse Model of Sickle Cell Disease.
abstract: Sickle retinopathy (SR) is a major cause of blindness in sickle cell disease (SCD). The genetic mutation responsible for SCD is known, however; oxidative stress and inflammation also figure prominently in the development and progression of pathology. Development of therapies for SR is hampered by the lack of (a) animal models that accurately recapitulate human SR and (b) strategies for noninvasive yet effective retinal drug delivery. This study addressed both issues by validating the Townes humanized SCD mouse as a model of SR and demonstrating the efficacy of oral administration of the antioxidant fumaric acid ester monomethyl fumarate (MMF) in the disease.
  
  
  
  In vivo ophthalmic imaging, electroretinography, and postmortem histological RNA and protein analyses were used to monitor retinal health and function in normal (HbAA) and sickle (HbSS) hemoglobin-producing mice over a one-year period and in additional HbAA and HbSS mice treated with MMF (15 mg/ml) for 5 months. Functional and morphological abnormalities and molecular hallmarks of oxidative stress/inflammation were evident early in HbSS retinas and increased in number and severity with age. Treatment with MMF, a known inducer of Nrf2, induced γ-globin expression and fetal hemoglobin production, improved hematological profiles, and ameliorated SR-related pathology. Innovation and Conclusion: United States Food and Drug Administration-approved formulations in which MMF is the primary bioactive ingredient are currently available to treat multiple sclerosis; such drugs may be effective for treatment of ocular and systemic complications of SCD, and given the pleiotropic effects, other nonsickle-related diseases in which oxidative stress, inflammation, and retinal vascular pathology figure prominently. Antioxid. Redox Signal. 25, 921-935.
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Wanwisa
authors.initials: W
authors.lastname: Promsote
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Folami Lamoke
authors.initials: FL
authors.lastname: Powell
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Satyam
authors.initials: S
authors.lastname: Veean
authors.affiliation: 2 Department of Ophthalmology, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Menaka
authors.initials: M
authors.lastname: Thounaojam
authors.affiliation: 3 Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Shanu
authors.initials: S
authors.lastname: Markand
authors.affiliation: 2 Department of Ophthalmology, The Medical College of Georgia at Augusta University , Augusta, Georgia .|4 The Culver Vision Discovery Institute, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Alan
authors.initials: A
authors.lastname: Saul
authors.affiliation: 2 Department of Ophthalmology, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Diana
authors.initials: D
authors.lastname: Gutsaeva
authors.affiliation: 2 Department of Ophthalmology, The Medical College of Georgia at Augusta University , Augusta, Georgia .|4 The Culver Vision Discovery Institute, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Manuela
authors.initials: M
authors.lastname: Bartoli
authors.affiliation: 2 Department of Ophthalmology, The Medical College of Georgia at Augusta University , Augusta, Georgia .|3 Department of Cellular Biology and Anatomy, The Medical College of Georgia at Augusta University , Augusta, Georgia .|4 The Culver Vision Discovery Institute, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Sylvia B
authors.initials: SB
authors.lastname: Smith
authors.affiliation: 5 Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center , Lubbock, Texas.
authors.forename: Vadivel
authors.initials: V
authors.lastname: Ganapathy
authors.affiliation: 1 Department of Biochemistry and Molecular Biology, The Medical College of Georgia at Augusta University , Augusta, Georgia .|2 Department of Ophthalmology, The Medical College of Georgia at Augusta University , Augusta, Georgia .|4 The Culver Vision Discovery Institute, The Medical College of Georgia at Augusta University , Augusta, Georgia .
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Martin
mesh_terms: D000284:Administration, Oral; D000755:Anemia, Sickle Cell / Q000097:blood / Q000150:complications* / Q000175:diagnosis; D000818:Animals; D001813:Blood-Retinal Barrier / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004596:Electroretinography; D005650:Fumarates / Q000008:administration & dosage*; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D012097:Repressor Proteins; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D012164:Retinal Diseases / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D055351:Retinal Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D005719:gamma-Globulins / Q000235:genetics / Q000378:metabolism
chemical_list: C407733:Bcl11a protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005650:Fumarates; D051267:NF-E2-Related Factor 2; D009687:Nuclear Proteins; D012097:Repressor Proteins; D042461:Vascular Endothelial Growth Factor A; D005719:gamma-Globulins; D018799:Intercellular Adhesion Molecule-1
keywords: Nrf2; fetal hemoglobin induction; inflammation; monomethyl fumarate; oxidative stress; retina