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病，影响世界人口的 2%。其特点是病变处有免疫浸润和角化过度，可以用处方药（例如外用维A酸）部分修复。尽管他们伟大潜在的，目前的外用类视黄醇药物通常以次优剂量使用，因为它们的副作用影响。所有第一代和第二代类维生素A都有常见的不良反应，包括皮肤刺激、光敏性和致畸性。虽然第三代类视黄醇似乎具有更好的致畸性安全性，但其皮肤不良反应（如红斑、鳞屑、干燥、瘙痒和烧灼感）并未得到改善，影响了 10-40% 的患者。为了发现副作用最小的类维生素A功能化合物，我们从传统上用于治疗皮肤病（重点是牛皮癣）的植物中筛选了天然化合物库。我们的研究产生了一种候选产品 (SBD.073)，其基因表达谱与人类皮肤替代品中的视黄醇（使用 DNA 微阵列）相似，但没有任何皮肤刺激，这是通过人体重复损伤斑贴试验确定的。在进一步的人体研究中，发现 SBD.073 不仅无刺激性和无光毒性，而且相反，可以保护皮肤免受紫外线引起的红斑。机制研究表明，与视黄醇类似，SBD.073 诱导 F9 细胞分化和真皮-表皮连接结构正常化，但与视黄醇不同的是，它不会刺激 RARG1（受体）的表达与皮肤刺激有关。此外，这种类维生素A类似物被发现具有优异的抗氧化和抗炎活性，并且无致突变性。在此，我们建议通过与现有局部类视黄醇治疗的比较研究来验证 SBD.073 是一种独特的候选药物，可大大改善银屑病的局部治疗。我们将结合使用银屑病相关检测，例如 TNF-a 和 IL-17/IL-22 - 刺激的器官型皮肤替代品，以及动物模型（小鼠尾部测试中的角化症、犀牛小鼠中的荨麻疹正常化以及 NMRI 小鼠中的致畸作用））证明 SBD.073 超过了当前局部类视黄醇治疗方式的治疗活性，同时具有首屈一指的安全性和耐受性。总而言之，该项目应该能够建立一个原理证明，证明 SBD.073 是第一个皮肤保护剂视黄醇类似物，可大大改善银屑病病变的局部治疗。