THU0046 Small molecule inhibitor of the wnt pathway (SM04755) as a potential topical treatment for psoriasis
Authors: V. Deshmukh, M. Pedraza, L. Lamangan, Y. Yazici
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Psoriasis (PSO) is an autoimmune disease, causing patches of thick, inflamed, scaly skin due to excessive proliferation of skin cells<sup>1</sup>. Wnt signalling plays an important role in PSO, regulating inflammation and keratinocyte proliferation. SM04755, a novel, topical small-molecule Wnt pathway inhibitor was previously shown to inhibit inflammation and keratinocyte proliferation <i>in vitro</i> and in an IMQ-induced mouse PSO model<sup>2</sup>. <h3>Objectives</h3> In this study, the effects of SM04755 on inflammation and skin health were evaluated in two models that closely resemble human PSO pathophysiology: reconstitution of ICR <i>scid</i> mice with minor histocompatibility mismatched naïve CD4<sup>+</sup> T lymphocytes<sup>3</sup> and an IL-23 intra-dermal injection model<sup>4</sup>. <h3>Methods</h3> For (A) immune reconstitution model, peripheral blood mononuclear cells were isolated from F<sub>2</sub> (BALB/c x 129/SvJ) mice and analysed by flow cytometry to identify H-2D<sup>d</sup> haplotype donor mice. CD4<sup>+</sup>/CD45RB<sup>Hi</sup> cells from donor mice spleens were purified and injected intravenously into CB17/ICR-Tac Prkdc/<i>scid</i> (ICR <i>scid</i>) mice (5 × 10<sup>5</sup> cells/mouse). Skin appearance and ear thickness were evaluated weekly. At the first visible PSO-like signs, mice were randomised and treated with SM04755 (400 µg/cm<sup>2</sup>) or vehicle. After 14 weeks, body and spleen weights were measured, and inflammation was evaluated by measuring cytokines (IL-1β, TNF-α, IL-6) in tissues from skin, ears, spleen and plasma using ELISA. Epidermal thickness and skin immune cell infiltration were histologically evaluated. For (B) the IL-23 model, rIL-23 was injected intra-dermally into mouse ears, every other day for 35 days. Mice were randomised on Day 16 and treated with SM04755 (400 µg/cm<sup>2</sup>) or vehicle or Clobetasol daily for 20 days. Ear thickness was measured every 3 days. Skin immune cell infiltration was histologically evaluated. <h3>Results</h3> (A) Immune reconstitution of ICR <i>scid</i> mice resulted in PSO-like signs, with skin lesions and increased thickness of the skin and ears. Treatment with topical SM04755 (400 µg/cm<sup>2</sup>) significantly (p&lt;0.01) decreased skin and ear thicknesses and improved skin appearance compared to vehicle. Body weights were significantly (p&lt;0.05) higher in treated compared to vehicle mice. SM04755 significantly reduced histologically measured epidermal thickness (p&lt;0.05) and immune cell infiltration in the skin compared to vehicle. Further, inflammatory cytokine levels in the skin, ears, spleen and plasma and spleen weight were significantly (p&lt;0.05) reduced in SM04755 treated animals compared with vehicle. (B) Intradermal IL-23 injection into mouse ears resulted in inflammation and ear thickening by day 16 compared to sham. Treatment with topical SM04755 (400 µg/cm<sup>2</sup>) significantly (p&lt;0.05) decreased ear thickness, immune cell infiltration, and improved appearance compared to vehicle. <h3>Conclusions</h3> In two mouse models of (A) minor histocompatibility mismatched T lymphocyte reconstitution-induced PSO and (B) IL-23 injection-induced PSO, topically applied SM04755 inhibited key pathophysiological features of PSO at macro- and microscopic levels, compared to vehicle. SM04755 has potential as a topical therapy for PSO. Clinical trials are ongoing. <h3>References</h3> [1] National PSO Foundation. [2] Deshmukh, et al. Arthritis Rheumatol. 2016;68(suppl 10). [3] Schon, et al. Nature Medicine, 1997Feb. [4] Mabuchiet al. J Immunol. 2011 Nov 15;187(10). <h3>Disclosure of Interest</h3> V. Deshmukh Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, M. Pedraza Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, L. Lamangan Shareholder of: Samumed, LLC, Employee of: Samumed, LLC, Y. Yazici Shareholder of: Samumed, LLC, Employee of: Samumed, LLC