Effective Gene Therapy of Mice with Congenital Erythropoietic Porphyria Is Facilitated by a Survival Advantage of Corrected Erythroid Cells

Achieving long-term expression of a therapeutic gene in a given hematopoietic lineage remains an important goal of gene therapy. Congenital erythropoietic porphyria (CEP) is a severe autosomal-recessive disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme...

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Published in:American journal of human genetics 2008-01, Vol.82 (1), p.113-124
Main Authors: Robert-Richard, Elodie, Moreau-Gaudry, François, Lalanne, Magalie, Lamrissi-Garcia, Isabelle, Cario-André, Muriel, Guyonnet-Dupérat, Véronique, Taine, Laurence, Ged, Cécile, de Verneuil, Hubert
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cell Survival
Disease Models, Animal
Erythrocytes
Female
Fundamental and applied biological sciences. Psychology
Gene therapy
General aspects. Genetic counseling
Genetic Therapy
Genetic Vectors
Genetics
Genetics of eukaryotes. Biological and molecular evolution
Hematopoietic Stem Cells
Lentivirus
Male
Medical disorders
Medical genetics
Medical sciences
Metabolic diseases
Mice
Mice, Inbred BALB C
Molecular and cellular biology
Other metabolic disorders
Pigments (porphyrias, hyperbilirubinemias...)
Porphyria, Erythropoietic - genetics
Porphyria, Erythropoietic - therapy
Rodents
Uroporphyrinogen III Synthetase - genetics
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Summary:Achieving long-term expression of a therapeutic gene in a given hematopoietic lineage remains an important goal of gene therapy. Congenital erythropoietic porphyria (CEP) is a severe autosomal-recessive disorder characterized by a deficiency in uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthetic pathway. We used a recently obtained murine model to check the feasibility of gene therapy in this disease. Lentivirus-mediated transfer of the human UROS cDNA into hematopoietic stem cells (HSCs) from Uros mut248 mice resulted in a complete and long-term enzymatic, metabolic, and phenotypic correction of the disease, favored by a survival advantage of corrected red blood cells. These results demonstrate that the cure of this mouse model of CEP at a moderate transduction level supports the proof of concept of a gene therapy in this disease by transplantation of genetically modified hematopoietic stem cells.
ISSN:0002-9297
1537-6605
DOI:10.1016/j.ajhg.2007.09.007