Erythropoietic Protoporphyria (EPP) is a rare inherited disease of heme biosynthesis that is characterized by extreme sensitivity to light. This condition results from mutations on the FECH gene, which causes the excess production of Protoporphyrin IX (PPIX) in the blood and skin. Protheragen specializes in the preclinical development of novel therapies for photosensitive genetic disorders, including EPP.
Introduction to Erythropoietic Protoporphyria
Erythropoietic Protoporphyria is an autosomal recessive disorder of heme synthesis which is characterized by a lack of ferrochelatase (FECH) – the last enzyme in the heme biosynthesis pathway. The disease is associated with an enzymatic block such that there is an excess synthesis, accumulation and absorption of PPIX in erythrocytes, plasma and, most importantly, in the skin. Erythropoietic Protoporphyria is characterized by excess PPIX in the body which, upon exposure to long wave ultraviolet light (UVA), absorbs photons and subsequently produces reactive oxygen species (ROS) and results in phototoxic reactions in the skin.
Fig.1 Production of protoporphyrin and chemical structure. (Leaf and Dickey, 2023)
Pathogenesis of Erythropoietic Protoporphyria
Erythropoietic protoporphyria (EPP) is classified as an uncommon condition within an inherited disorder spectrum. The defect is predominantly associated with mutations in the FECH gene, and results in a partial deficiency of the ferrochelatase enzyme which catalyzes the terminal step in heme synthesis. Consequently, there is an excess accumulation of protoporphyrin IX in red blood cells, plasma, and the skin. Protoporphyrin reacts with sunlight, visible light in particular, and non-blistering photosensitivity along with skin pain and inflammation occurs. Liver involvement is reported in some of the patients due to excess protoporphyrin in the liver which can result in liver failure. The prevalence is estimated to 1:75,000 – 200,000 diagnosed individuals and is likely underdiagnosed due to diverse symptoms and infrequency.
Therapeutics Development for Erythropoietic Protoporphyria
| Therapeutic Strategy |
Therapeutic Target |
Mechanism of Action |
Key Clinical Data |
Development Stage |
| Afamelanotide (Scenesse®) |
Melanocortin-1 Receptor (MC1R) |
Activates MC1R to increase melanin synthesis via cAMP/PKA pathway, enhancing photoprotection |
Clinically significant reduction in phototoxic pain |
Approved |
| Ursodeoxycholic Acid |
FXR / Bile Acid Transporters |
Activates FXR to upregulate bile acid efflux pumps (e.g., BSEP/MRP2), promoting protoporphyrin excretion |
Meaningful reduction in hepatic protoporphyrin |
Phase II |
| Lentiviral FECH Gene Therapy |
Ferrochelatase Gene (FECH) |
Delivers functional FECH cDNA to restore ferrochelatase enzyme activity in HSCs |
Complete protoporphyrin correction in models |
Phase I |
| Gene Editing |
FECH Mutation Sites |
Uses sgRNA-guided gene editing to precisely correct disease-causing FECH mutations |
Partial enzyme activity restoration in models |
Preclinical |
| WEE1 Kinase Inhibition |
WEE1 kinase |
Adavosertib (AZD1775) |
Induces synthetic lethality in RECQL4-deficient osteosarcoma cells. |
Preclinical |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Protheragen offers an integrated approach to erythropoietic protoporphyria therapeutic development, providing comprehensive preclinical solutions that set us apart in the industry. Our specialists use sophisticated platforms for expedited drug and diagnostic development, working in synergy with advanced therapeutic and advanced disease models.
Disease Model Development for Erythropoietic Protoporphyria
Protheragen develops EPP pathology-relevant 2D cell models, 3D skin models, and animal models that accurately reflect the FECH deficiency, PPIX accumulation, and subsequent phototoxicity. Our models are specifically designed to recapitulate oxidative stress, inflammation, and cellular damage pathways to advance dermatology-focused therapeutic discovery.
2D Cell Models & 3D Skin Models
- EPP patient-derived iPSC line
- FECH-deficient erythroid progenitor cells
- Hepatocyte-spheroid co-culture
- 3D phototoxic skin equivalent
- Light-responsive epidermal organoid
Animal Models Development
- Fechm1Pas spontaneous mutant mouse
- Liver-specific Fech KO mouse
- Humanized FECH p.M343I transgenic rat
- ALAS2 gain-of-function zebrafish
- Phototoxicity phenotyping rabbit
DMPK and Drug Safety Evaluation Services
Protheragen offers comprehensive DMPK and drug safety evaluation services, specifically designed to accelerate the preclinical development of novel therapies for erythropoietic protoporphyria. We are committed to generating robust data to support the efficacy and safety of your innovative drug candidates.
In Vitro ADME Services
- Metabolic Stability
- Reaction Phenotyping
- CYP450 Inhibition/Induction
- Blood/Plasma Partitioning
As a preclinical research service provider focused on rare dermatological and multi-organ genetic disorders, Protheragen accelerates therapeutic development for systemic conditions like erythropoietic protoporphyria. We provide FECH gene target validation, EPP-specific disease modeling, drug safety evaluation and DMPK services.
Contact us to explore how our end-to-end solutions can advance your erythropoietic protoporphyria research.
References
- Kuo, N., et al. "The Histamine Pathway Is a Target to Treat Hepatic Experimental Erythropoietic Protoporphyria." Cell Mol Gastroenterol Hepatol 19.6 (2025): 101463.
- Leaf, R. K., and A. K. Dickey. "How I Treat Erythropoietic Protoporphyria and X-Linked Protoporphyria." Blood 141.24 (2023): 2921-31.
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