4 results on '"Ged, C"'
Search Results
2. Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria.
- Author
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Blouin JM, Ged C, Lalanne M, Lamrissi-Garcia I, Morice-Picard F, Costet P, Daher R, Moreau-Gaudry F, Bedel A, Puy H, Gouya L, Karim Z, and Richard E
- Subjects
- 5-Aminolevulinate Synthetase antagonists & inhibitors, 5-Aminolevulinate Synthetase biosynthesis, 5-Aminolevulinate Synthetase genetics, Adult, Anemia, Hemolytic etiology, Animals, CRISPR-Cas Systems, Cell Line, Cell Line, Tumor, Disease Models, Animal, Erythroid Cells drug effects, Erythroid Cells metabolism, Female, Gene Knock-In Techniques, Humans, Iron metabolism, Iron Overload etiology, Leukemia, Erythroblastic, Acute pathology, Mice, Peripheral Blood Stem Cells drug effects, Peripheral Blood Stem Cells metabolism, Photosensitivity Disorders etiology, Porphyria, Acute Intermittent metabolism, Porphyria, Erythropoietic complications, Porphyrins biosynthesis, RNA Interference, RNA, Small Interfering pharmacology, Anemia, Hemolytic drug therapy, Deferiprone therapeutic use, Iron Chelating Agents therapeutic use, Iron Overload drug therapy, Photosensitivity Disorders drug therapy, Porphyria, Erythropoietic drug therapy
- Abstract
Congenital erythropoietic porphyria (CEP) is an inborn error of heme synthesis resulting from uroporphyrinogen III synthase (UROS) deficiency and the accumulation of nonphysiological porphyrin isomer I metabolites. Clinical features are heterogeneous among patients with CEP but usually combine skin photosensitivity and chronic hemolytic anemia, the severity of which is related to porphyrin overload. Therapeutic options include symptomatic strategies only and are unsatisfactory. One promising approach to treating CEP is to reduce the erythroid production of porphyrins through substrate reduction therapy by inhibiting 5-aminolevulinate synthase 2 (ALAS2), the first and rate-limiting enzyme in the heme biosynthetic pathway. We efficiently reduced porphyrin accumulation after RNA interference-mediated downregulation of ALAS2 in human erythroid cellular models of CEP disease. Taking advantage of the physiological iron-dependent posttranscriptional regulation of ALAS2, we evaluated whether iron chelation with deferiprone could decrease ALAS2 expression and subsequent porphyrin production in vitro and in vivo in a CEP murine model. Treatment with deferiprone of UROS-deficient erythroid cell lines and peripheral blood CD34+-derived erythroid cultures from a patient with CEP inhibited iron-dependent protein ALAS2 and iron-responsive element-binding protein 2 expression and reduced porphyrin production. Furthermore, porphyrin accumulation progressively decreased in red blood cells and urine, and skin photosensitivity in CEP mice treated with deferiprone (1 or 3 mg/mL in drinking water) for 26 weeks was reversed. Hemolysis and iron overload improved upon iron chelation with full correction of anemia in CEP mice treated at the highest dose of deferiprone. Our findings highlight, in both mouse and human models, the therapeutic potential of iron restriction to modulate the phenotype in CEP., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
3. ALAS2 acts as a modifier gene in patients with congenital erythropoietic porphyria.
- Author
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To-Figueras J, Ducamp S, Clayton J, Badenas C, Delaby C, Ged C, Lyoumi S, Gouya L, de Verneuil H, Beaumont C, Ferreira GC, Deybach JC, Herrero C, and Puy H
- Subjects
- 5-Aminolevulinate Synthetase metabolism, Amino Acid Sequence, Anemia, Sideroblastic genetics, Anemia, Sideroblastic metabolism, Anemia, Sideroblastic pathology, Base Sequence, Child, Preschool, Electrophoresis, Polyacrylamide Gel, Family Health, Female, Genetic Diseases, X-Linked genetics, Genetic Diseases, X-Linked metabolism, Genotype, Humans, Infant, Kinetics, Male, Molecular Sequence Data, Pedigree, Porphyria, Erythropoietic metabolism, Porphyria, Erythropoietic pathology, Protoporphyria, Erythropoietic genetics, Protoporphyria, Erythropoietic metabolism, Sequence Homology, Amino Acid, Severity of Illness Index, Spectrophotometry, Uroporphyrinogen III Synthetase metabolism, Uroporphyrinogens metabolism, 5-Aminolevulinate Synthetase genetics, Mutation, Missense, Porphyria, Erythropoietic genetics, Uroporphyrinogen III Synthetase genetics
- Abstract
Mutations in the uroporphyrinogen III synthase (UROS) gene cause congenital erythropoietic porphyria (CEP), an autosomal-recessive inborn error of erythroid heme biosynthesis. Clinical features of CEP include dermatologic and hematologic abnormalities of variable severity. The discovery of a new type of erythroid porphyria, X-linked dominant protoporphyria (XLDPP), which results from increased activity of 5-aminolevulinate synthase 2 (ALAS2), the rate-controlling enzyme of erythroid heme synthesis, led us to hypothesize that the CEP phenotype may be modulated by sequence variations in the ALAS2 gene. We genotyped ALAS2 in 4 unrelated CEP patients exhibiting the same C73R/P248Q UROS genotype. The most severe of the CEP patients, a young girl, proved to be heterozygous for a novel ALAS2 mutation: c.1757 A > T in exon 11. This mutation is predicted to affect the highly conserved and penultimate C-terminal amino acid of ALAS2 (Y586). The rate of 5-aminolevulinate release from Y586F was significantly increased over that of wild-type ALAS2. The contribution of the ALAS2 gain-of-function mutation to the CEP phenotype underscores the importance of modifier genes underlying CEP. We propose that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders.
- Published
- 2011
- Full Text
- View/download PDF
4. 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.
- Author
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Fontanellas A, Mazurier F, Moreau-Gaudry F, Belloc F, Ged C, and de Verneuil H
- Subjects
- Animals, B-Lymphocytes transplantation, Cell Line, Transformed, Cell Transformation, Viral, Coculture Techniques, Flow Cytometry, Herpesvirus 4, Human, Humans, Male, Mice, Mice, Mutant Strains, Microscopy, Fluorescence, Porphyria, Hepatoerythropoietic genetics, Porphyria, Hepatoerythropoietic therapy, Selection, Genetic, Transfection, Ultraviolet Rays, Uroporphyrinogen Decarboxylase genetics, B-Lymphocytes enzymology, Genetic Therapy, Porphyria, Hepatoerythropoietic enzymology, Uroporphyrinogen Decarboxylase deficiency
- 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.
- Published
- 1999
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