Congenital erythropoietic porphyria (CEP) is an unaddressed orphan disease caused by a rare genetic disorder leading to accumulation of uro/coproporphyrin-I (uro-I) in tissues due to inhibition of the enzyme uroporphyrinogen-III synthase. Clinical manifestations of CEP include bone fragility, severe photosensitivity, and photo-mutilation. Currently there is no specific treatment for CEP, except bone marrow transplantation.
Researchers at Rutgers University have shown that fluorescent porphyrins cause protein aggregation that interferes with protein function, and consequently cellular function. They have found that uro-I accumulation leads to protein aggregation and CEP-related bone phenotype, and have developed a zebrafish model that phenocopies features of CEP. As in human patients, uro-I accumulated in the bones of zebrafish, leads to impaired bone development. In an osteoblast-like cell line, uro-I decreased mineralization, aggregated bone matrix proteins, activated endoplasmic reticulum stress and disrupted autophagy.
Using high-throughput drug screening, the researchers have identified acitretin, a second-generation retinoid, that reduces uro-I accumulation and its deleterious effects on bones. Another retinoid, tretinoin showed porphyrin clearance in zebrafish. These findings provide a new CEP experimental model and describe the use of retinoids as potential repurposed therapeutics for CEP.
- Model and related technology can be used to reduce R&D costs and drug development timeline via the use of FDA-approved drugs acitretin and tretinoin.
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- Bragazzi Cunha, J., Elenbaas, J.S., Maitra, D. et al. (2021). Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models. Scientific Reports. Link.
- Maitra D, Cunha JB, Elenbaas JS, Bonkovsky HL, Shavit JA, Omary MB. (2019). Porphyrin-induced protein oxidation and aggregation as a mechanism of porphyria associated cell injury. Cell Mol Gastroenterol Hepatol. Link.