Novel therapy for Netherton syndrome

内瑟顿综合征的新疗法

基本信息

批准号：
8977549
负责人：
JAMES W LARRICK
金额：
$ 22.5万
依托单位：
PANORAMA RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8977549
关键词：
Adult Adverse event Affinity Animal Model Animals Anti-Inflammatory Agents Anti-inflammatory Antibiotics Antibodies Atopic Dermatitis Bacterial Infections Binding Cells Characteristics Chronic Complex Data Dehydration Disease Dissociation Drug Kinetics Enzymes Epidermis Epithelial Failure to Thrive Genetic study Human Human Engineering Human Genetics Immunosuppressive Agents In Vitro Infant Inflammation Keyhole Limpet Hemocyanin Kininogenase Libraries Life Metastatic to Modeling Monoclonal Antibodies Mutation Newborn Infant Peptide Hydrolases Pharmaceutical Preparations Phase Protease Inhibitor Proteins Recurrence Reporting Rosacea Safety Serine Protease Skin Small Interfering RNA Squamous cell carcinoma Stratum corneum Symptoms Syndrome Testing Therapeutic Therapeutic Intervention Time Tissue Kallikrein Tissues Toxic effect Trypsin Work base cohesion desmoglein 1 effective therapy human kallikrein 5 human monoclonal antibodies human tissue in vitro activity inhibitor/antagonist neonate novel novel therapeutics pancreatic elastase II pre-clinical premature prevent public health relevance skin disorder skin irritation tissue culture

项目摘要

DESCRIPTION (provided by applicant): Netherton syndrome (NS) is one of the most severe heritable skin disorders of neonates, with life-threatening symptoms that result from a defective skin barrier. Severe complications in infants include recurrent bacterial infections, dehydration, and failure to thrive. In adults, NS is a chronic, debilitating condition with no effective treatmet. Current therapies (anti-inflammatory drugs, immunosuppressants, antibiotics, and drugs for symptomatic relief) are only modestly effective, and often cause unacceptable adverse events, particularly with long-term use. Recently, the cause of NS was identified as mutations in an epidermal protease inhibitor, LEKTI. At neutral pH, in the deep stratum corneum (SC), LEKTI binds and inhibits Kallikrein-5 (KLK5). In normal epidermis, LEKTI inhibits KLK5 through a pH-dependent interaction. In the superficial SC, where the pH is 4.5- 5, this complex dissociates, permitting KLK5 to proteolytically activate additional epidermal kallikreins, KLK7 and KLK14 as well as elastase-2 (ELA2). These proteases degrade corneodesmosomal proteins, leading to shedding of superficial cells. Recent data from human genetic studies, animal models, and siRNA knockdown of LEKTI in organotypic human tissue culture, establish unregulated KLK5 activity as the underlying cause of NS. An inhibitory antibody to KLK5 can provide an effective treatment for NS by blocking the KLK5 protease cascade in the SC. During this Phase I project, we will identify an inhibitory anti-KLH human monoclonal antibody (humAb). We will evaluate inhibitory activity in vitro, using an organotypic human skin culture model. This work has the potential to result in a new therapeutic for NS, by alleviating the life-threatening skin barrier deficits in the newborn, and reducing skin irritation and inflammation in adults. This humAb may also be effective against other dermatological disorders, including atopic dermatitis, that involve activated KLK5.

描述（由申请人提供）：内瑟顿综合征（NS）是新生儿最严重的遗传性皮肤病之一，皮肤屏障缺陷会导致婴儿出现危及生命的症状，严重并发症包括反复细菌感染、脱水和衰竭。对于成年人来说，NS 是一种慢性、使人衰弱的疾病，目前没有有效的治疗方法（抗炎药、免疫抑制剂、抗生素和缓解症状的药物）。效果不佳，并且经常引起不可接受的不良事件，特别是长期使用时，最近发现 NS 的原因是表皮蛋白酶抑制剂 LEKTI 的突变，在中性 pH 值下，LEKTI 在深层角质层 (SC) 中结合。并抑制激肽释放酶-5 (KLK5) 在正常表皮中，LEKTI 通过 pH 依赖性相互作用抑制 KLK5。 5 后，该复合物解离，使 KLK5 能够通过蛋白水解激活额外的表皮激肽释放酶、KLK7 和 KLK14 以及弹性蛋白酶-2 (ELA2)，这些蛋白酶会降解角桥粒蛋白，从而导致来自人类遗传研究和动物模型的表面细胞脱落。，以及在器官型人体组织培养中 LEKTI 的 siRNA 敲低，确定不受调控的 KLK5 活性是根本原因KLK5 的抑制性抗体可以通过阻断 SC 中的 KLK5 蛋白酶级联来提供 NS 的有效治疗。在该 I 期项目中，我们将鉴定一种抑制性抗 KLH 人单克隆抗体 (humAb)。这项工作有可能通过减轻新生儿危及生命的皮肤屏障缺陷和减少皮肤来开发 NS 的新疗法。这种 humAb 也可能对其他皮肤病有效，包括特应性皮炎。激活KLK5。