Novel Skin Protectant Retinoid for the Treatment of Psoriasis

描述(申请人提供)：牛皮癣是一种慢性皮肤病，影响2%的世界人口。它的特点是皮损中有免疫浸润物和角化过度，可以用处方药部分治愈，如局部应用维甲酸。尽管他们很棒 潜在的、目前局部使用的维甲酸类药物通常是以次优剂量使用的，因为它们的侧面 效果。副作用，包括皮肤刺激性、光敏性和致畸性，在所有第一代和第二代维甲酸中都是常见的。虽然第三代维甲酸似乎具有更好的致畸安全性，但其皮肤不良反应，如红斑、结垢、干燥、瘙痒和灼热并未得到改善，影响到10%-40%的患者。为了发现副作用最小的类维A酸类功能化合物，我们筛选了传统上用于治疗皮肤病的植物中的天然化合物库，重点是牛皮癣。我们的研究产生了一种候选产品(SBD.073)，其所需的基因表达谱与人类皮肤替代品中的视黄醇相似(使用DNA微阵列)，但没有任何皮肤刺激性，这是通过对人类的重复侮辱斑贴试验确定的。在进一步的人体研究中，人们发现SBD.073不仅没有刺激性和光毒性，相反，它还可以保护皮肤免受紫外线诱导的红斑的伤害。机制研究表明，与视黄醇类似，SBD.073诱导F9细胞分化和真皮-表皮连接的正常化结构，但与视黄醇不同，它不刺激受体RARG1的表达 与皮肤刺激有关。此外，该维甲酸类似物具有良好的抗氧化和抗炎活性，且无致突变性。在这里，我们建议在一项与现有局部维甲酸治疗的比较研究中，验证SBD.073是极大改善牛皮癣局部治疗的唯一候选药物的原则证据。我们将结合使用与银屑病相关的检测方法，如肿瘤坏死因子-a和IL-17/IL-22刺激的器官型皮肤替代品，以及动物模型(小鼠尾部试验中的角化矫正、犀牛小鼠的荨麻疹正常化和NMRI小鼠的致畸作用)来证明SBD.073超过了当前局部维甲酸治疗方法的治疗活性，同时具有一流的安全性和耐受性。综上所述，该项目将确立SBD.073是第一种皮肤保护剂视黄醇类似物的原则证明，用于极大地改进牛皮癣皮损的局部治疗。

DESCRIPTION (provided by applicant): Psoriasis is a chronic skin disease affecting 2% of the world population. It is characterized by immune infiltrates in lesions and hyperkeratosis, and can be partially remediated with prescription medicines, such as topical retinoids. Despite their great potential, current topical retinoid drugs are typically used at suboptimal doses, due to their side effects. Adverse effects, which include skin irritation, photosensitivity and teratogenicity are common to all 1st and 2nd generation retinoids. While the 3rd generation of retinoids appears to have a better teratogenicity safety profile, its skin-adverse effects such as erythema, scaling, dryness, pruritus, and burning are not improved, affecting 10-40% of patients. In an attempt to discover retinoid-like functional compounds with minimal adverse effects, we screened libraries of natural compounds from plants traditionally used for the treatment of skin diseases, with the emphasis on psoriasis. Our research yielded one product candidate (SBD.073) with desired similar gene expression profile to retinol in human skin substitutes (using DNA microarrays) but without any skin irritation, as determined by repeat insult patch test in humans. In further human studies, SBD.073 has been found to be not only non-irritant and non-phototoxic, but, to the contrary, to protect skin from UV-induced erythema. Mechanistic studies showed that, similarly to retinol, SBD.073 induced F9 cell differentiation and normalized structure of the dermal-epidermal junction, but unlike retinol, it did not stimulate the expression of RARG1 - the receptor implicated in skin irritation. Moreover, this retinoid analogue was found to have an excellent anti oxidant and anti-inflammatory activity and no mutagenicity. Here, we propose to validate the proof of principle that SBD.073 is a unique drug-candidate for a greatly improved topical treatment of psoriasis in a comparative study with the existing topical retinoid treatments. We will use a combination of psoriasis-relevant assays, such as TNF-a and IL-17/IL-22 - stimulated organotypic skin substitutes, and animal models (orthokeratosis in mouse tail test, urticuli normalization in rhino mouse and teratogenesis in NMRI mouse) to demonstrate that SBD.073 exceeds the therapeutic activity of current topical retinoid treatment modalities, while having second- to-none safety and tolerance profile. Taken together, this project should result in the establishment of a proof of principle that SBD.073 is the first skin-protectant retinol analogue fo a greatly improved topical therapy of psoriatic lesions.