title: Reductions in serum vitamin A arrest accumulation of toxic retinal fluorophores: a potential therapy for treatment of lipofuscin-based retinal diseases.
abstract: OBJECTIVE
  Excessive accumulation of lipofuscin is observed in numerous degenerative retinal diseases. A toxic vitamin A-based fluorophore (A2E) present within lipofuscin has been implicated in the death of RPE and photoreceptor cells. Here, we used an animal model that manifests accelerated lipofuscin accumulation (ABCA4-/- mutant) to evaluate the efficacy of a therapeutic approach based on reduction of serum retinol.
  
  
  METHODS
  N-(4-hydroxyphenyl)retinamide (HPR) potently and reversibly reduces serum retinol. The interaction of HPR with retinol binding protein (RBP) and transthyretin was studied by spectrofluorometry and size-exclusion chromatography. To assess the effects of HPR on visual cycle retinoids and A2E biosynthesis, HPR was chronically administered to ABCA4-/- mice. Mice were evaluated using biochemical, electrophysiological, and morphologic techniques.
  
  
  RESULTS
  Administration of HPR to ABCA4-/- mice caused immediate, dose-dependent reductions in serum retinol and RBP. Chronic administration produced commensurate reductions in visual cycle retinoids and arrested accumulation of A2E and lipofuscin autofluorescence in the RPE. Physiologically, HPR treatment caused modest delays in dark adaptation. Chromophore regeneration kinetics, light sensitivity of photoreceptors, and phototransduction processes were normal. Histologic examinations showed no alteration of retinal cytostructure or morphology.
  
  
  CONCLUSIONS
  These findings demonstrate the vitamin A-dependent nature of A2E biosynthesis and validate a novel therapeutic approach with potential to halt the accumulation of lipofuscin fluorophores in the eye.
authors.affiliation: Jules Stein Eye Institute, University of California, Los Angeles, California, USA.
authors.forename: Roxana A
authors.initials: RA
authors.lastname: Radu
authors.forename: Yun
authors.initials: Y
authors.lastname: Han
authors.forename: Tam V
authors.initials: TV
authors.lastname: Bui
authors.forename: Steven
authors.initials: S
authors.lastname: Nusinowitz
authors.forename: Dean
authors.initials: D
authors.lastname: Bok
authors.forename: Jay
authors.initials: J
authors.lastname: Lichter
authors.forename: Ken
authors.initials: K
authors.lastname: Widder
authors.forename: Gabriel H
authors.initials: GH
authors.lastname: Travis
authors.forename: Nathan L
authors.initials: NL
authors.lastname: Mata
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D003623:Dark Adaptation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004596:Electroretinography; D017313:Fenretinide / Q000008:administration & dosage*; D008062:Lipofuscin / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D010775:Photic Stimulation; D010857:Pigment Epithelium of Eye / Q000378:metabolism; D011228:Prealbumin / Q000378:metabolism; D011726:Pyridinium Compounds / Q000378:metabolism*; D012160:Retina / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D012176:Retinoids / Q000378:metabolism*; D012177:Retinol-Binding Proteins / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D014801:Vitamin A / Q000097:blood*
chemical_list: C112040:A2-E (N-retinylidene-N-retinylethanolamine); D018528:ATP-Binding Cassette Transporters; C512841:Abca4 protein, mouse; D008062:Lipofuscin; D011228:Prealbumin; D011726:Pyridinium Compounds; D012176:Retinoids; D012177:Retinol-Binding Proteins; D014801:Vitamin A; D017313:Fenretinide