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Santaris, Collaborators Report on Role of miR-21 in Psoriasis

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A team of Spanish researchers this week published a new report implicating microRNA-21 in psoriasis and demonstrating that 8-mer locked nucleic acids targeting the miRNA could improve symptoms of the disease in a mouse model.

The findings, the investigators stated, point to the therapeutic potential of miR-21 inhibition, although they caution that the robustness of the approach still needs to be compared with that of existing biologic-based psoriasis drugs.

They also add to a growing body of data on the efficiency and specificity of short LNAs — dubbed "tiny LNAs" by their developer Santaris Pharma, which collaborated on the study — for miRNA silencing.

Although the exact cause of psoriasis is unknown, dysregulated interactions between keratinocytes, immune cells, and inflammatory mediators have been shown to play a key role. Also implicated is tumor necrosis factor-alpha (TNFa), a proinflammatory cytokine produced by skin keratinocytes and inflammatory cells that activate the various immune cells that contribute to the disease.

TNF-alpha shedding is crucial to activating TNFa signaling, and tissue inhibitor of matrix metalloproteinase 3 (TIMP-3) — an inhibitor of the TNA-alpha sheddase TACE — has been shown to be downregulated in psoriasis.

To that end, a number of TNAa inhibitors are used to treat the disorder, including Enbrel (etanercept), Remicade (infliximab), and Humira (adalimumab), according to the research team. Yet, the side effects of these products have prompted the search for alternative therapeutic options, they noted.

To explore the possible involvement of miRNAs in psoriasis, the investigators examined biopsies from skin donors with lesional and non-lesional variants of the condition, looking for the expression of miRNAs known to target TIMP-3, they wrote in a paper appearing in Science Translational Medicine.

In nearly all samples analyzed, miR-21 was found to be increased in epidermal cells, which correlated with a downregulation of epidermal TIMP-3 mRNA. "Moreover, miR-21 upregulation and TIMP-3 downregulation correlated with enhanced TNFa mRNA expression in the lesional epidermis," they wrote.

Further experimentation confirmed the observations, establishing that miR-21 expression is increased in psoriatic epidermis and correlates with TIMP-3 downregulation and an increase in TACE activity.

Aiming to identify a causal role for miR-21 in psoriasis, the investigators created tiny LNAs against the miRNA and intradermally injected them into the affected areas of the tail of a mouse model of the disease. Scrambled LNAs and saline were used as controls.

Histological evaluation showed that miR-21 inhibition led to reduced epidermal thickening and reduced keratinocyte proliferation, while qRT-PCR analysis indicated that the anti-miR-21 tiny LNAs induced mRNA expression of miR-21 targets, including TIMP-3. Further, treatment reduced TNFa mRNA expression and epidermal TACE activity.

In order to test the therapeutic potential of their findings, the scientists took advantage of a preclinical model in which patient-derived psoriatic biopsies of lesional skin were transplanted into severe combined immunodeficient mice.

The animals were treated with either miR-21-targeting tiny LNAs, scrambled oligos, saline, or etanercept via intradermal injection into the lesions every 48 hours for four weeks, and the samples were analyzed.

"Histological analyses and epidermal thickening quantification demonstrated that miR-21 inhibition provided a beneficial effect in 8 of 11 psoriasis cases as demonstrated by reduced epidermal thickening," according to the Science Translational Medicine paper. "A similar effect was observed when comparing miR-21 inhibition with TNFa inhibition using etanercept." Inhibition of miR-21 also resulted in upregulation of TIMP-3 and downregulation of TNFa.

Overall, the findings point to a causal role for miR-21 in the pathogenesis of epidermal hyperplasia in psoriasis, the researchers concluded in their paper. Moreover, "blocking miR-21 and its target TIMP-3 may be a potential therapeutic strategy for treating psoriasis."

Additional work remains to be done to fully explore this approach, however, including the study of miR-21 inhibition in additional biopsies from patients with different subtypes of psoriasis. The benefits of targeting miR-21 also need to be compared to that for anti-TNFa biologics currently used, as well as new emerging therapies, they added.

Although Santaris has not publicly disclosed that it is pursuing a miRNA-based treatment for psoriasis, the company has reported on the therapeutic potential of tiny LNAs before, including a presentation at the annual Oligonucleotide Therapeutics Society meeting in 2010, which featured miR-21 data.

The next year, Santaris and collaborators at Cold Spring Harbor Laboratory published a report showing that tiny LNAs could downregulate entire miRNA families and be delivered into solid tumors.

And last year, the company and scientists from Massachusetts General Hospital published a paper showing that tiny LNAs could knock down the miR-33 family and influence cholesterol levels in non-human primates.

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