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Citation Information: J Clin Invest. 2025. https://doi.org/10.1172/JCI181875.
Abstract
Erythropoietic protoporphyria (EPP) is a genetic disorder typically resulting from decreased ferrochelatase (FECH) activity, the last enzyme in heme biosynthesis. Patients with X-linked protoporphyria (XLPP) have an overlapping phenotype caused by increased activity of 5-aminolevulinic acid synthase 2 (ALAS2), the first enzyme in erythroid heme synthesis. In both cases, protoporphyrin IX (PPIX) accumulates in erythrocytes and secondarily in plasma and tissues. Patients develop acute phototoxicity reactions upon brief exposure to sunlight. Some also suffer from chronic liver disease, and a small fraction develop acute cholestatic liver failure. Therapeutic options are limited, and none, save hematopoietic stem cell transplantation, directly targets erythroid PPIX accumulation. Bitopertin is an investigational orally available small molecule inhibitor of the erythroid cell surface glycine transporter GLYT1. We establish the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirm a marked reduction of PPIX in erythroblasts derived from EPP patients. We demonstrate that bitopertin also reduces erythrocyte and plasma PPIX accumulation in vivo in mouse models of both EPP and XLPP. Finally, the reduction in erythroid PPIX ameliorates liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.
Authors
Sarah Ducamp, Min Wu, Juan Putra, Dean R. Campagna, Yi Xiang, Vu Hong, Matthew M. Heeney, Amy K. Dickey, Rebecca K. Leaf, Mark D. Fleming, Brian MacDonald, Paul J. Schmidt
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ISSN: 0021-9738 (print), 1558-8238 (online)