Iron chelation rescues hemolytic anemia and skin photosensitivity in congenital erythropoietic porphyria

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...

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Published in:Blood 2020-11, Vol.136 (21), p.2457-2468
Main Authors: Blouin, Jean-Marc, Ged, Cécile, Lalanne, Magalie, Lamrissi-Garcia, Isabelle, Morice-Picard, Fanny, Costet, Pierre, Daher, Raêd, Moreau-Gaudry, François, Bedel, Aurélie, Puy, Hervé, Gouya, Laurent, Karim, Zoubida, Richard, Emmanuel
Format: Article
Language:English
Subjects:
5-Aminolevulinate Synthetase - antagonists & inhibitors
5-Aminolevulinate Synthetase - biosynthesis
5-Aminolevulinate Synthetase - genetics
Adult
Anemia, Hemolytic - drug therapy
Anemia, Hemolytic - etiology
Animals
Cell Line
Cell Line, Tumor
CRISPR-Cas Systems
Deferiprone - therapeutic use
Disease Models, Animal
Erythroid Cells - drug effects
Erythroid Cells - metabolism
Female
Gene Knock-In Techniques
Genetics
Human genetics
Humans
Iron - metabolism
Iron Chelating Agents - therapeutic use
Iron Overload - drug therapy
Iron Overload - etiology
Leukemia, Erythroblastic, Acute - pathology
Life Sciences
Mice
Peripheral Blood Stem Cells - drug effects
Peripheral Blood Stem Cells - metabolism
Photosensitivity Disorders - drug therapy
Photosensitivity Disorders - etiology
Porphyria, Acute Intermittent - metabolism
Porphyria, Erythropoietic - complications
Porphyria, Erythropoietic - drug therapy
Porphyrins - biosynthesis
RNA Interference
RNA, Small Interfering - pharmacology
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Summary: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. •Substrate reduction therapy by iron restriction–mediated downregulation of ALAS2 efficiently reduces porphyrin accumulation in CEP.•Iron chelation decreases porphyrin overload and reverses hemolytic anemia and skin photosensitivity in CEP mice. [Display omitted]
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2020006037