ORNITHINE-DELTA-AMINOTRANSFERASE EXPRESSION AND ORNITHINE METABOLISM IN CULTURED EPIDERMAL-KERATINOCYTES - TOWARD METABOLIC SINK THERAPY FOR GYRATE ATROPHY

There is now strong evidence that the chorioretinal degeneration assoc iated with ornithine-delta-aminotransferase (OAT) deficiency is a cons equence of hyperornithinemia. Therefore development of a metabolic sys tem for clearing ornithine from the circulation is being pursued as a potential treatment. The skin is considered an attractive location for such a metabolic system because autologous cells can be safely and ea sily utilized. This study was undertaken to determine the ornithine me tabolizing capacity of epidermal keratinocytes expressing normal and s uperphysiologic amounts of OAT. The data show the overexpression of OA T in keratinocytes cultured from a gyrate atrophy patient restores orn ithine metabolism and results in a rate of ornithine disappearance fro m the medium that is significantly higher than the rate of disappearan ce from the medium bathing normal keratinocytes. In addition, OAT acti vity determined in soluble protein prepared from sonicates suggests th at the capacity to maintain plasma ornithine within the normal range i s contained within an accomplishable graft of keratinocytes overexpres sing OAT. However, the actual rate of ornithine disappearance from the media was significantly less than predicted from enzyme activity assa ys. Following ornithine metabolite production by intact cells suggests that ornithine metabolism is limited primarily by clearance of downst ream metabolites, as opposed to substrate delivery.