Department of Pathology, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts.
Alnylam Pharmaceuticals, Inc., Cambridge, Massachusetts.
Am J Hematol. 2020 May;95(5):492-496. doi: 10.1002/ajh.25743. Epub 2020 Feb 7.
Reduced ferrochelatase activity in erythropoietic protoporphyria (EPP) causes the accumulation of protoporphyrin IX (PPIX) leading to acute cutaneous photosensitivity and liver injury. Many EPP patients also have a mild hypochromic, microcytic anemia and iron deficiency. Iron deficiency can lead to decreased PPIX accumulation in another erythropoietic porphyria, congenital erythropoietic porphyria (CEP). Expression of the iron regulatory peptide hepcidin is negatively regulated by the serine protease TMPRSS6. Hepcidin induction by siRNA-mediated inhibition of TMPRSS6 expression reduces iron availability and induces iron deficiency. To interrogate the therapeutic potential of iron deficiency to modify EPP, we treated an ethylnitrosourea-induced mouse model of EPP, Fech , with a GalNAc-conjugated Tmprss6 siRNA and PPIX levels, anemia and iron parameters were monitored. The GalNAc-RNAi therapeutic reduces Tmprss6 expression and induces mild iron deficiency in Fech animals. However, decreases in erythrocyte PPIX levels and liver PPIX accumulation were not seen. These results indicate short-term induction of iron deficiency, at least in a murine model of EPP, does not lead to decreased PPIX production.
血红素加氧酶活性降低导致红细胞生成性原卟啉症（EPP）中卟啉 IX（PPIX）的积累，从而导致急性皮肤光敏感和肝损伤。许多 EPP 患者还伴有轻度低色素性、小细胞性贫血和缺铁。缺铁可导致另一种红细胞生成性卟啉症，先天性红细胞生成性卟啉症（CEP）中 PPIX 积累减少。铁调节肽hepcidin 的表达受丝氨酸蛋白酶 TMPRSS6 的负调控。通过 siRNA 介导的 TMPRSS6 表达抑制诱导 hepcidin，可降低铁的可用性并诱导缺铁。为了探讨缺铁对 EPP 进行修饰的治疗潜力，我们用 GalNAc 缀合的 Tmprss6 siRNA 处理乙基硝基亚硝基胍诱导的 EPP 小鼠模型，监测 PPIX 水平、贫血和铁参数。GalNAc-RNAi 治疗可降低 Fech 动物中 Tmprss6 的表达并诱导轻度缺铁。然而，红细胞 PPIX 水平和肝脏 PPIX 积累的降低并未观察到。这些结果表明，至少在 EPP 的小鼠模型中，短期诱导缺铁不会导致 PPIX 产生减少。
