ArticleThe Journal of clinical investigation2025
The GLYT1 inhibitor bitopertin mitigates erythroid PPIX production and liver disease in erythroid protoporphyria.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
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Who cites it
4 citing papers in PubMed.
- Genetic testing to distinguish X-linked protoporphyria from erythropoietic protoporphyria informed iron replacement therapy leading to reversal of severe protoporphyric hepatopathy.Molecular genetics and metabolism reports · 2026Article
- Understanding the Clinical Spectrum of the Cutaneous and Acute Hepatic Porphyrias.American journal of clinical dermatology · 2026Review
- Glycine transport inhibitors for the treatment of chronic pain conditions: the time is ripe for clinical evaluation!Frontiers in molecular neuroscience · 2026Article
- Blocking extracellular glycine uptake mediated by GlyT1 mitigates protoporphyria.The Journal of clinical investigation · 2025Article
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Authors and funding
12 authors.
Funding
No grant is acknowledged in the PubMed record.
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 experience 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 established the bitopertin PPIX inhibitory half-maximal effective concentration in a human erythroblast EPP model and confirmed a marked reduction of PPIX in erythroblasts derived from patients with EPP. We demonstrate that bitopertin also reduced erythrocyte and plasma PPIX accumulation in vivo in both EPP and XLPP mouse models. Finally, the reduction in erythroid PPIX ameliorated liver disease in the EPP mouse model. Altogether, these data support the development of bitopertin to treat patients with EPP or XLPP.
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