Correction of uroporphyrinogen decarboxylase deficiency (hepatoerythropoietic porphyria) in Epstein-Barr virus-transformed B-cell lines by retrovirus-mediated gene transfer: fluorescence-based selection of transduced cells.

Abstract	Hepatoerythropoietic porphyria (HEP) is an inherited metabolic disorder characterized by the accumulation of porphyrins resulting from a deficiency in uroporphyrinogen decarboxylase (UROD). This autosomal recessive disorder is severe, starting early in infancy with no specific treatment. Gene therapy would represent a great therapeutic improvement. Because hematopoietic cells are the target for somatic gene therapy in this porphyria, Epstein-Barr virus-transformed B-cell lines from patients with HEP provide a model system for the disease. Thus, retrovirus-mediated expression of UROD was used to restore enzymatic activity in B-cell lines from 3 HEP patients. The potential of gene therapy for the metabolic correction of the disease was demonstrated by a reduction of porphyrin accumulation to the normal level in deficient transduced cells. Mixed culture experiments demonstrated that there is no metabolic cross-correction of deficient cells by normal cells. However, the observation of cellular expansion in vitro and in vivo in immunodeficient mice suggested that genetically corrected cells have a competitive advantage. Finally, to facilitate future human gene therapy trials, we have developed a selection system based on the expression of the therapeutic gene. Genetically corrected cells are easily separated from deficient ones by the absence of fluorescence when illuminated under UV light.
Authors	A Fontanellas, F Mazurier, F Moreau-Gaudry, F Belloc, C Ged, H de Verneuil
Journal	Blood (Blood) Vol. 94 Issue 2 Pg. 465-74 (Jul 15 1999) ISSN: 0006-4971 [Print] United States
PMID	10397714 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Uroporphyrinogen Decarboxylase
Topics	Animals B-Lymphocytes (enzymology, transplantation) Cell Line, Transformed Cell Transformation, Viral Coculture Techniques Flow Cytometry Genetic Therapy Herpesvirus 4, Human Humans Male Mice Mice, Mutant Strains Microscopy, Fluorescence Porphyria, Hepatoerythropoietic (enzymology, genetics, therapy) Selection, Genetic Transfection Ultraviolet Rays Uroporphyrinogen Decarboxylase (deficiency, genetics)

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