María Jiménez and Juan Guinea-Viniegra

Nearly 2% of people worldwide chronically suffer from itchy and painful patches on their bodies, the manifestation of psoriasis, an incurable inflammatory disease in which immune cells infiltrate the skin and release molecules called cytokines that stimulate the skin cells to grow too rapidly. Treatments such as corticosteroids and immunosuppressants can help alleviate mild forms of the disease, and newer antibody-based therapies provide some relief for some of the most severe cases, but some patients fail to respond to these treatments or experience harmful side effects. Now, a new study shows that inhibiting a specific microRNA—a short bit of genetic material that influences the production of proteins in cells—appears to be an effective psoriasis treatment in mice, leaving researchers hopeful that this therapeutic approach will one day be tested in clinical trials.

Psoriasis researchers have known for some time that the levels of a microRNA called miR-21 are elevated in the skin lesions of patients with psoriasis. To determine whether miR-21 plays a crucial role in the disease, a team of scientists led by Erwin Wagner at the Spanish National Cancer Research Centre in Madrid inhibited these genetic elements using an anti-miR-21 treatment. The anti-miR-21 molecules are tiny strands of nucleotides that specifically glom onto miR-21 and prevent it from functioning. Wagner and his colleagues injected this treatment into the skin of mice bearing grafts of diseased tissue from human patients with psoriasis. The anti-miR-21 reduced the thickness of the human skin lesions by about half, a response similar to that obtained using the antibody-based psoriasis therapy etanercept (commercially available from California-based Amgen as Enbrel).

The anti-miR-21therapy appears to work by increasing the levels of an enzyme called tissue inhibitor of matrix metalloproteinase 3 (TIMP-3), which reduces the activity of the enzyme responsible for producing the inflammatory cytokine that triggers the abnormal growth of skin cells in psoriasis. The researchers report their findings online today in Science Translational Medicine.

“This is a completely new way of dealing with the disease,” says Andor Pivarcsi, an immunologist at the Karolinska Institutet in Stockholm who studies psoriasis and was not involved in the study. He adds that the small size of the inhibitor might allow it to be applied topically to the skin, which is a formidable barrier to most substances unless they are small, uncharged, and relatively fat-soluble. For patients who don’t respond to the available psoriasis therapies, “this could be a new hope,” he says.

Remaining barriers

Wagner says that his team has not yet figured out how to get the inhibitor to cross the skin barrier, aside from simply injecting it just beneath the surface as they did in their new study. And systemic delivery—an approach that has proven successful in a phase 2 trial of an anti-miR therapy (the first microRNA-based therapeutic to reach clinical trials) for hepatitis C virus infection—is not an option, says study co-author Juan Guinea-Viniegra, because less than 1% of the drug would be delivered to the skin and the majority would instead end up in the liver. “One would have to inject vast amounts of the anti-miRNA compounds to achieve a therapeutic effect in the skin,” Guinea-Viniegra says. Nevertheless, the team is optimistic that the therapy, in the right formulation, could one day prove useful for some patients. “I don’t think we want to stop here,” Wagner says.

Indeed, interest in the development of drugs that target microRNAs has exploded in recent years. For example, Santaris Pharmaceuticals, the Danish company that supplied Wagner’s team with anti-miR-21, has partnered with Colorado-based MiRagen Therapeutics in pre-clinical studies of several additional anti-miR agents for cardiovascular and other diseases. In addition, the delivery of short strands of nucleotides that mimic rather than inhibit the function microRNAs, a strategy known as microRNA replacement therapy, have been used to thwart tumors in mice. At this rate, it may not be too much longer before we have a better idea of whether microRNA-based therapeutics will be viable drug candidates.

**Correction (28 February): In an earlier version of this story, one individual’s name was spelled incorrectly. The correct spelling is Andor Pivarcsi. “MicroRNA” was also misspelled in the title of the article. Nature Medicine regrets the errors.