Psoriasis Drug Soriatane Eases Bone Defects in Zebrafish CEP Model

Aisha I Abdullah PhD avatar

by Aisha I Abdullah PhD |

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Soriatane (acitretin), a medication normally used to treat the skin disorder psoriasis, was found to alleviate bone defects in a new zebrafish model of congenital erythropoietic porphyria, or CEP, a study reports.

The medicine worked to ease bone defects driven by the accumulation of the molecule uroporphyrin-I in the bones.

In addition to providing the porphyria community with a new animal model of the disease — important for research — the scientists noted that data from this study supports the therapeutic potential of repurposing Soriatane for the treatment of CEP.

The study, “Acitretin mitigates uroporphyrin-induced bone defects in congenital erythropoietic porphyria models,” was published in the journal Scientific Reports

CEP, also known as Günther disease, is the rarest form of porphyria, and is characterized by severe light sensitivity — called photosensitivity — and frequent skin infections. Those infections can lead to scarring and bone loss, and to deformities in the hands, feet, and face.

The disorder is caused by mutations in the UROS or GATA1 genes, which lead to the accumulation of uroporphyrin-I, known as uro-I, an intermediate molecule in the heme production pathway in different cells and tissues in the body. Of note, heme is a molecule that red blood cells need to transport oxygen throughout the body.

Here, researchers had speculated that the buildup of uro-I causes proteins clumps (aggregates) and subsequent tissue damage in CEP. To test this hypothesis, they developed a new zebrafish model of CEP, created by injecting young fish larvae with uro-I.

As in humans, uro-I accumulated in the animals’ bone cells, causing bone defects and severe photosensitivity in young zebrafish. Uro-I-injected fish also exhibited growth impairments in facial and vertebrae bones. 

The investigators then used the new zebrafish model to screen 1,280 small molecule candidates for their ability to treat uro-I-induced CEP. Soriatane, an oral retinoid normally used to treat psoriasis — an autoimmune disorder that mainly affects the skin — was found to lower uro-I accumulation in the animals’ bones.

One day after zebrafish larvae were injected with uro-I and immediately transferred to media containing Soriatane, the researchers noticed significant reductions in uro-I bone accumulation. These reductions were accompanied by increased excretion, or release, of uro-I into the media.

To test Soriatane’s ability to reverse the effects of uro-I-induced CEP, the investigators transferred uro-I-injected larvae to Soriatane media 24 hours later. The animals were then examined after 24 hours of treatment. As found previously, Soriatane increased the excretion of uro-I; however, it had no impact on bone porphyrin accumulation.

“Using our novel zebrafish CEP model, we demonstrated that acitretin attenuated uro-I-mediated bone damage by modulating the dynamics of uro-I bone binding and excretion,” the researchers wrote.

Next, the researchers turned to human cancer cells with properties similar to those of osteoblasts — cells that form new bone tissue — to explore the molecular mechanisms underlying uro-I-mediated bone damage.

Uro-I treatment disrupted the normal bone formation processes, causing the clumping up of proteins that form the bone’s matrix. It also induced stress in the endoplasmic reticulum, the cell compartment where proteins are produced.  

Moreover, treatment with uro-I caused such severe photosensitivity in osteoblast-like human cells that the researchers were required to protect them from light in order to prevent cell death. 

While Soriatane treatment did not restore mineralization in uro-I-treated cells, it lowered endoplasmic reticulum stress and normalized autophagy — the process by which cells break down and recycle components they no longer need.

“The management of CEP is challenging, with current therapeutic options focusing on bone marrow/hematopoietic stem cell transplantation, and by avoidance of sun and light exposure,” the investigators wrote.

“Currently there are no known pharmaceuticals that act by clearance of uro-I, and in this regard acitretin provides a novel approach,” they wrote.

By using a therapy already approved for other diseases, scientists can build upon the medicine’s previous research and development efforts. Since already approved medications already have been tested in humans, they can more quickly be ready for clinical trials for new indications.

“Acitretin also offers a drug repurposing advantage since it is already approved for psoriasis treatment,” the researchers wrote.