The approved antifungal Ciclopirox is a potential therapy to stabilize and enhance the function of the uroporphyrinogen III synthase, the enzyme whose defective activity causes congenital erythropoietic porphyria (CEP).
This is one example of how therapies already approved for one disorder can be repurposed for other diseases.
The study, “Repurposing ciclopirox as a pharmacological chaperone in a model of congenital erythropoietic porphyria” was published in the journal Science Translational Medicine.
Porphyrias are a group of metabolic disorders that occur because of defects in the production of heme, an important part of hemoglobin — the protein that transports oxygen in red blood cells.
CEP, also known as Günther’s disease, arises because of defective activity of a particular enzyme, called uroporphyrinogen III synthase. It is one of the key enzymes in the production of heme.
The enzyme’s poor activity results in the accumulation of porphyrins — natural chemicals found in the body. While the amount of porphyrins is low during normal heme production, levels can increase and reach toxic amounts if one of the enzymes in heme production is defective.
In CEP, the buildup of porphyrins, which occurs especially in the skin, results in anemia, abnormal enlargement of the spleen, and skin lesions.
There is no cure for congenital erythropoietic porphyria. Available therapies help manage symptoms, but do not address the root of the disease.
Treatments tried over the years include blood transfusions, surgical removal of the spleen, and bone marrow transplants, but all carry a risk of complications or their effects are short-lived.
“There are currently no approved pharmacological treatments for CEP, highlighting the need to identify novel therapeutic strategies that address the underlying pathology and affect the quality of life of these patients,” researchers said.
A potential strategy to counteract the degradation of uroporphyrinogen III synthase is using the so-called chemical chaperones, which bind to a protein and stabilize it.
Researchers at the Center for Cooperative Research in Biosciences (CIC bioGUNE), Spain and colleagues screened a library of 2,500 chemical fragments to identify those that could help stabilize the uroporphyrinogen III synthase. They then compared the hits from the screen against a U.S. Food and Drug Administration-approved library of 1,800 therapies.
The outcome of their analysis identified the synthetic antifungal Ciclopirox (sold under many brand names, including Penlac and Loprox) as a compound capable of binding to the enzyme and stabilizing it.
Treatment of cells and later of a CEP mouse model showed that the antifungal medicine restored enzymatic activity and was able to alleviate most of the animal clinical symptoms.
Ciclopirox was given to the mice in food pellets. Researchers measured the levels of porphyrins in the blood each week until the last test, which was made at day 45 after treatment. At this stage, Ciclopirox reduced the concentration of a type 1 porphyrin in the livers of the mice by 40 percent and prevented enlargement of the spleen.
Overall, “our findings establish a possible line of therapeutic intervention against congenital erythropoietic porphyria,” the study concluded.