Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gyrate atrophy (GA) of the choroid and retina is an autosomal recessive chorioretinal degeneration, caused by deficiency of the mitochondrial matrix enzyme ornithine-delta-aminotransferase (OAT). This deficiency results in the accumulation of ornithine in the body fluids and leads to hyperornithinemia. Although the clinical phenotype is largely confined to the eye, OAT deficiency is a systemic disorder. With the final goal of applying gene therapy to this human genetic disease, we have established an in vitro model to test the correction of OAT enzymatic deficiency in mammalian cells, using OAT recombinant retroviruses. We report the construction of several Moloney murine leukemia virus (MoMLV)-based recombinant retrovirus vectors, in which the human OAT cDNA was placed under the transcriptional control of the mouse phosphoglycerate kinase (PGK) promoter or under the enhancer-promoter regulatory element derived from the MoMLV long terminal repeat (LTR). The retrovirus constructs were packaged in the PG13-GALV cell line and used to transduce C9, an OAT deficient cell line derived from Chinese hamster ovary cells (CHO-K1). We show that the recombinant retrovirus transfers the human OAT (hOAT) gene into C9. Expression of the hOAT gene in the transduced C9 deficient cell line exceeded the OAT mRNA level and enzymatic activity of endogenous human fibroblasts.
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PMID:Correction of ornithine-delta-aminotransferase deficiency in a Chinese hamster ovary cell line mediated by retrovirus gene transfer. 771 30

Gyrate atrophy is a progressive blindness associated with deficiency of ornithine aminotransferase (OAT). The strategy of using an autologous keratinocyte graft, modified to express high levels of OAT as an ornithine-catabolizing skin-based enzyme sink, is investigated. Two OAT-containing retroviral vectors were constructed with or without a resistance gene. When packaged in a retroviral vector particle generated with the gibbon ape leukemia (GALV) virus envelope (PG13), these vectors could readily transduce >50% of target keratinocytes. The transduced keratinocytes in culture expressed up to 75-fold more OAT than normal control keratinocytes and these gene-modified cells extracted [14C]ornithine more efficiently than controls. The vector prepared without neo transduced cells more efficiently and led to higher levels of OAT expression than the neo-containing vector. Ornithine catabolism was maintained at high levels when the transduced patient keratinocytes were differentiated in vitro as a multilayered cutaneous organoid.
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PMID:Retrovirus-mediated gene transfer of ornithine-delta-aminotransferase into keratinocytes from gyrate atrophy patients. 941 60