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(Investigative Ophthalmology and Visual Science. 2005;46:4393-4401.)
© 2005 by The Association for Research in Vision and Ophthalmology, Inc.
DOI:  10.1167/iovs.05-0820
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Reductions in Serum Vitamin A Arrest Accumulation of Toxic Retinal Fluorophores: A Potential Therapy for Treatment of Lipofuscin-Based Retinal Diseases

Roxana A. Radu,1 Yun Han,2 Tam V. Bui,2 Steven Nusinowitz,1 Dean Bok,1,3,4 Jay Lichter,2 Ken Widder,2 Gabriel H. Travis,1,5 and Nathan L. Mata1,2

1From the Jules Stein Eye Institute, University of California, Los Angeles, California; 2Sytera, Inc., La Jolla, California; and the 3Department of Neurobiology, 4Brain Research Institute, and 5Department of Biological Chemistry, University of California, School of Medicine, Los Angeles, California.

PURPOSE. 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.




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