An existing antifungal drug, ciclopirox (CPX), has been shown to improve symptoms associated with congenital erythropoietic porphyria – the rarest type of porphyria. The study was conducted using a mouse model of the disease, the team’s findings were published in Science Translational Medicine.
What is porphyria?
Porphyria is the term used to describe a group of metabolic disorders that are caused by inborn errors of heme biosynthesis. Each porphyria is caused by a specific enzyme deficiency occurring within the heme biosynthetic pathway. Porphyria can be categorized as either acute or cutaneous. Acute porphyria sufferers experience acute attacks of porphyria because of ALA and PBG build up that causes damage to the nerves. Those with cutaneous porphyria experience sensitivity to sunlight on exposed skin.
Congenital erythropoietic porphyria (CEP), also known as Günther's disease belongs to the cutaneous porphyria group. It is an extremely rare autosomal recessive multi-organ disease caused by a deficiency in an enzyme called uroporphyrinogen III synthase (UROIIIS), which leads to the accumulation of Type 1 porphyrins. Porphyrins form the basis of several substances in the body, for example hemoglobin – the protein responsible for transporting O2 in red blood cells.
CEP symptoms include hemolysis (rupturing of red blood cells), anemia, enlargement of the spleen, skin scarring, and disfiguring phototoxic skin lesions – often manifesting during infancy.
The severity of the skin symptoms is determined by the quantity of porphyrins in the affected tissue and the degree of light exposure.
"CEP is a devastating disease, that is usually treated palliatively (i.e. avoid sun exposure, bone fracture and skin degradation). The currently available therapeutic treatments are intrusive, dangerous and only partially alleviate the symptoms. In this context, our approach paves the way for a potential non-invasive therapy that may bring direct benefit to the patients." explains Óscar Millet, Protein Stability and Inherited Disease Laboratory, CIC bioGUN, corresponding author of the study.
Therapeutically targeting congenital erythropoietic porphyria
In an attempt to find a novel pharmacological treatment for CEP, the researchers screened thousands of drug candidates to determine their ability to interact with UROIIIS. One such candidate, ciclopirox (CPX), a synthetic antimicrobial, successfully bound to the UROIIIS enzyme at an allosteric site without disturbing UROIIIS’s catalytic function. Once bound it restored the enzyme’s activity.
"We used a bottom-up approach that aimed to test several thousand compounds, to generate a short list of hits. The goal was to then perform thorough biophysical characterization of the hits, so they quickly evolved to lead compounds and to a drug candidate." says Millet.
In a genetic mouse model of CEP, animals administered CPX regained function of the enzyme. Many of the CEP-associated symptoms were alleviated using sub-toxic concentrations of the drug suggesting that CPX could be a promising treatment for CEP.
More specifically they found that treatment with CPX:
- Reduced the porphyrin levels in red blood cells, as well as the liver and urine.
- Increased the levels of PROTO IX (a downstream heme precursor) which is an indirect measure of homeostasis restoration of the heme pathway.
- Reduced enlargement of the spleen which is an indirect measure of a reduction in circulating porphyrins.
- Displayed a therapeutic effect on numerous damaged tissues including the spleen, kidney and liver.
To determine whether CPX could be successfully repurposed as a treatment for this devastating disease, the drug’s efficacy and safety would need to be further investigated in a clinical setting, in humans with CEP.
Urquiza, P., et al. Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria. Sci. Transl. Med. (2018) DOI: 10.1126/scitranslmed.aat7467