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 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.
Robert-Richard
Elodie
E
Inserm U876, Institut Fédératif de Recherche 66, Bordeaux, F-33000 France.
Moreau-Gaudry
François
F
Lalanne
Magalie
M
Lamrissi-Garcia
Isabelle
I
Cario-André
Muriel
M
Guyonnet-Dupérat
Véronique
V
Taine
Laurence
L
Ged
Cécile
C
de Verneuil
Hubert
H
D000818:Animals; D002470:Cell Survival; D004195:Disease Models, Animal; D004912:Erythrocytes; D005260:Female; D015316:Genetic Therapy; D005822:Genetic Vectors; D006412:Hematopoietic Stem Cells; D016086:Lentivirus; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D017092:Porphyria, Erythropoietic / Q000235:genetics* / Q000628:therapy; D014576:Uroporphyrinogen III Synthetase / Q000235:genetics*
D014576:Uroporphyrinogen III Synthetase