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Abstract
Background Systemic lupus erythematosus (SLE) is 9 times more prevalent in females than in males, suggesting a possible role for X-linked genes in disease onset and progression. Toll-like receptor (TLR7) is an X-encoded innate immune sensor that detects RNA degradation products to promote inflammatory cytokine and interferon production during viral infection. While aberrant TLR7 activity has long been implicated in the aetiology of systemic autoimmunity, a recent study published in Nature has now definitively linked gain-of-function mutations in TLR7 with human lupus.1 There are currently no approved therapeutic inhibitors of TLR7, making this an urgent unmet need. We have developed novel synthetic, RNA-like trimeric oligonucleotides that bind to TLR7 with low nanomolar potency to effectively block its activation by RNA.
Methods Daily application of Aldara cream, containing the TLR7 agonist Imiquimod, induces an inflammatory skin phenotype in mice that resembles psoriasis or cutaneous lupus erythematosus (CLE). Aldara cream was applied topically to the back and ear of C57/BL6J mice directly following, or not, application of TLR7-inhibitory trimeric oligonucleotides formulated in F127 Pluronic gel. Mice were scored daily for the appearance and severity of skin inflammation. After four days, mice were humanely euthanised for multiplex ELISA and qPCR analysis of serum cytokines and inflammatory gene signatures in the skin, respectively.
Results Topical treatment with the TLR7-inhibitory trimeric oligonucleotides greatly ameliorated disease severity (measured by scaling and redness on the back and ear, as well as dermal thickening of the ear) and also led to a significant reduction in both NF-κB-dependent and Type I interferon-stimulated genes in the skin.
Conclusions Our novel TLR7-inhibitory trimeric oligonucleotides represent a promising new class of therapeutics for the treatment of TLR7-driven inflammation in skin manifestations of autoimmunity, for example, psoriasis and CLE.
References
Brown et al. Nature 2022;605:349–356.
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