04191 Inhibition of glycine transporter 1 reduces EPP phototoxicity in a mouse model of erythropoietic protoporphyria (EPP)
Year: 2024
Type: conference-paper
Abstract: Erythropoietic protoporphyria (EPP) is a genetic disorder typically caused by reduced activity of ferrochelatase (FECH), the enzyme that catalyzes the final step in heme biosynthesis. EPP phototoxicity occurs when the photosensitive metal-free protoporphyrin IX (PPIX) in erythrocytes and skin is exposed to irradiation from sunlight, absorbs photons, and produces reactive oxygen species (ROS) that damage the skin and subdermal layers. EPP patients suffer from acute and severe phototoxicity after sun exposure, significantly impacting their quality of life.The Fechm1Pas/Fechm1Pas homozygous mice (EPP mice) retain approximately 5% residual ferrochelatase activity due to a severe homozygous loss-of-function mutation. EPP mice develop protoporphyria characterized by elevated PPIX levels in red blood cells (RBCs) and liver, liver fibrosis, and cutaneous phototoxicity, manifested as skin lesions when these mice are exposed to light with excitation wavelength of PPIX (395 to 410 nM) (Wang, 2019).Glycine transporter 1 (GlyT1) mediates the import of glycine, a precursor for heme synthesis, to erythroid cells. The GlyT1 inhibitor bitopertin has been shown to reduce whole blood PPIX levels in EPP patients in Phase 2 clinical studies (Dickey, 2024; Ross, 2024) and in animal models (Wu, 2022).This study evaluated whether GlyT1 inhibition can ameliorate phototoxicity via downregulating PPIX levels in the Fechm1Pas/Fechm1Pas EPP mice. The EPP mice were administered vehicle or a selective small molecule inhibitor of GlyT1, DISC-C, at 15 mg/kg, p.o., twice per day, for 18 days. GlyT1 inhibition reduced PPIX levels in RBCs by 43% and 37% on Day 14 and Day 18, respectively. On Day 14 of treatment, hair was removed from the backs of the EPP mice, and all mice were exposed to light with wavelength of 395 nM, 588 ±10% lumens (lm)/m2 for 30 minutes. Mice administered vehicle developed progressively worsening skin lesions over the observation period from Day 14 to Day 18, with 51.2% exposed skin area developing skin lesions at 4 days post light exposure (Day 18). In contrast, mice administered DISC-C developed skin lesions in 9.2% of exposed skin area, suggesting GlyT1 inhibition reduced phototoxicity in Fechm1Pas/Fechm1Pas homozygous mice. Additionally, lower percentage of the area with skin lesions correlated with lower PPIX levels in RBCs.In conclusion, this study demonstrated that by inhibiting glycine uptake into erythroid precursors and reducing PPIX levels in RBCs, GlyT1 inhibitor treatment could reduce EPP phototoxicity in the EPP mouse model. These data support the rationale for treating EPP patients with GlyT1 inhibitors.References Dickey A, et al. EHA Library. 06/13/2024; 419662; P1575.Ross G, et al. EHA Library. 06/13/2024; 419656; P1569.Wang P, et al. Sci Adv. 2019;5(9):eaaw6127.Wu M, et al. Blood. 2022;140(Suppl1):8192–8193.
Authors: Yi Xiang, Yue Chen, Scott Reisman, Srikanth Venkatraman, Hua Yang, Brian MacDonald, Min Wu
Institution: Disc Medicine, Inc. (United States)
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402696196