Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina

Correction of ornithine accumulation prevents retinal degeneration in a mouse model of gyrate atrophy of the choroid and retina

^*Howard Hughes Medical Institute and ^‡Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and ^†Scheie Eye Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Edited by Jeremy Nathans, Johns Hopkins University School of Medicine, Baltimore, MD, and approved November 15, 1999 (received for review September 13, 1999)

Abstract

Deficiency of ornithine-δ-aminotransferase (OAT) in humans results in gyrate atrophy of the choroid and retina (GA), an autosomal recessive disorder characterized by ornithine accumulation and a progressive chorioretinal degeneration of unknown pathogenesis. To determine whether chronic, systemic reduction of ornithine can prevent this form of retinal degeneration, we used an arginine-restricted diet to maintain long term reduction of ornithine in a mouse model of OAT-deficiency (Oat ^−/−) produced by gene targeting. We evaluated the mice over a 12-month period by measurement of plasma amino acids, electroretinograms, and retinal histologic and ultrastructural studies. We found that an arginine-restricted diet substantially reduces plasma ornithine levels and completely prevents retinal degeneration in Oat ^−/−. This result indicates that ornithine accumulation is a necessary factor in the pathophysiology of the retinal degeneration in GA and that restoration of OAT activity in retina is not required for effective treatment of GA.

Footnotes

↵ § To whom reprint requests should be addressed at: PCTB 802, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. E-mail: dvalle{at}jhmi.edu.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

OAT,

ornithine-δ-aminotransferase;

GA,

gyrate atrophy of the choroid and retina;

RPE,

retinal pigment epithelium