Novel Skin Protectant Retinoid for the Treatment of Psoriasis

用于治疗牛皮癣的新型皮肤保护剂类维生素A

基本信息

批准号：
8449026
负责人：
KRYS BOJANOWSKI
金额：
$ 14.95万
依托单位：
SUNNY BIODISCOVERY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8449026
关键词：
Adapalene Adult Adverse effects Affect All-Trans-Retinol Animal Model Anti-Inflammatory Agents Anti-inflammatory Antioxidants Archives Avage Basement membrane Biological Assay Biopsy Burn injury Case Study Cell Differentiation process Chimera organism Chronic Clinical Comparative Study Consensus DNA Microarray Chip Data Defect Dermal Dermatitis Dose Drug Industry Drug Kinetics Dryness Ear Enzyme-Linked Immunosorbent Assay Epithelial Erythema Exencephalies Exhibits Fetal Resorption Gene Expression Gene Expression Profile Generations Hematoxylin and Eosin Staining Method Histology Homeostasis Horns Human Hyperkeratosis IL17 gene Immune Immunohistochemistry Industry Inferior Infiltration Inflammation Inflammatory Inflammatory Response Interleukin-17 Lesion Libraries Limb structure Materials Testing Measures Medicinal Plants Medicine Methods Modality Modeling Mus NMRI Mouse Names Parakeratosis Patch Tests Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Photosensitivity Phototherapy Phototoxicity Plants Play Population Pregnancy Preparation Procedures Process Property Pruritus Psoriasis Regimen Research Retinoids Role Safety Skin Skin Substitutes Specificity Staining method Stains Structure Sunscreening Agents T-Lymphocyte T-Lymphocyte Subsets TNF gene Tail Tazarotene Testing Therapeutic Thick Tissues Translating Tretinoin UV induced Ultraviolet B Radiation Visual absorption analog base chronic autoimmune disease comparative compliance behavior cytokine drug candidate effective therapy improved in vivo innovation interleukin-22 irritation keratinization keratinocyte malformation mouse model novel pregnant public health relevance receptor research study response skin disorder skin irritant skin irritation success

项目摘要

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.

描述（由申请人提供）：牛皮癣是一种慢性皮肤疾病，影响世界人口的2％。它的特征在于病变和高性病中的免疫浸润，并且可以用处方药（例如局部类维生素）进行部分修复。尽管他们很棒电势，当前的局部类维生素性药物通常以次优剂量使用，因为它们的侧面效果。不良反应，包括皮肤刺激，光敏性和致畸性在所有第一代和第二代视网膜类似中都是常见的。虽然第三代类维生素类动物似乎具有更好的伤亡性安全性，但其皮肤不良反应（例如红斑，缩放，干燥，瘙痒和燃烧）并没有得到改善，影响了10-40％的患者。为了尝试发现具有最小不良反应的类视感样的功能化合物，我们从传统上用于治疗皮肤病的植物中筛选了天然化合物的库，重点是牛皮癣。我们的研究产生了一个候选产品（SBD.073），其在人体皮肤替代物中具有与视黄醇相似的基因表达谱（使用DNA微阵列），但没有任何皮肤刺激，这是通过人类重复侮辱贴剂测试确定的。在进一步的人类研究中，已经发现SBD.073不仅是非虹吸和非毒性毒性的，而且相反，可以保护皮肤免受紫外线诱发的红斑。机械研究表明，与视黄醇相似，SBD.073诱导了F9细胞分化和皮肤表皮结的归一化结构，但与视黄醇不同，它没有刺激RARG1的表达 - 受体的表达与皮肤刺激有关。此外，发现类维生素类似物具有出色的抗氧化剂和抗炎活性，没有诱变。在这里，我们建议验证SBD.073的原理证明，是与现有局部性视网膜类动物治疗的比较研究中，是对牛皮癣的局部局部治疗的独特候选人。我们将结合牛皮癣相关的测定法，例如TNF-A和IL-17/IL-22-刺激的器官型皮肤替代品和动物模型（小鼠尾部试验中的正差，在NMRI小鼠中的犀牛小鼠的荨麻疹归一化），以表明SBD的活动超过了SBD.073的活动，该模型超过了，既超过sbd.073又有型号。第二次安全和公差概况。综上所述，该项目应导致建立SBD.073的原则证明。073是第一个皮肤蛋白酶视黄醇模拟，可以极大地改善银屑病病变的局部疗法。