Effective gene therapy of mice with congenital erythropoietic porphyria is facilitated by a survival advantage of corrected erythroid cells.

Abstract

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.

• Authors: Elodie Robert-Richard, François Moreau-Gaudry, Magalie Lalanne, Isabelle Lamrissi-Garcia, Muriel Cario-André, Véronique Guyonnet-Dupérat, Laurence Taine, Cécile Ged, Hubert de Verneuil
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 82 Issue 1 Pg. 113-24 (Jan 2008) ISSN: 1537-6605 [Electronic] United States
• PMID: 18179890 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Uroporphyrinogen III Synthetase

Topics

• Animals
• Cell Survival
• Disease Models, Animal
• Erythrocytes
• Female
• Genetic Therapy
• Genetic Vectors
• Hematopoietic Stem Cells
• Lentivirus
• Male
• Mice
• Mice, Inbred BALB C
• Porphyria, Erythropoietic (genetics, therapy)
• Uroporphyrinogen III Synthetase (genetics)