Key Points

  • 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

Congenital erythropoietic porphyria (CEP) is an inborn error of heme synthesis resulting from uroporphyrinogen III synthase (UROS) deficiency and the accumulation of non-physiological porphyrin isomer I metabolites. Clinical features are heterogeneous among CEP patients but usually combine skin photosensitivity and chronic hemolytic anemia, whose severity is related to porphyrin overload. Therapeutic options are essentially symptomatic and unsatisfactory. One promising strategy to treat 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 RNAi-mediated downregulation of ALAS2 in human erythroid cellular models of CEP disease. Taking advantage of the physiological iron-dependent post-transcriptional 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 of UROS-deficient erythroid cell lines and peripheral blood CD34+-derived erythroid cultures from a CEP patient with deferiprone inhibited iron-dependent protein ALAS2 and IRP2 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 a 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.

This content is only available as a PDF.

Article PDF first page preview

Article PDF first page preview
You do not currently have access to this content.