Novel therapy for Netherton syndrome

 描述(申请人提供)：Netherton综合征(NS)是新生儿中最严重的遗传性皮肤病之一，其皮肤屏障缺陷导致危及生命的症状。婴儿的严重并发症包括反复的细菌感染、脱水和无法茁壮成长。在成年人中，NS是一种慢性、衰弱的疾病，没有有效的治疗方法。目前的治疗方法(抗炎药物、免疫抑制剂、抗生素和缓解症状的药物)仅有一定的效果，而且往往会导致不可接受的不良事件，特别是长期使用的话。最近，NS的原因被确定为表皮蛋白酶抑制剂Lekti的突变。在中性pH条件下，在角质层深层(SC)，Lekti结合并抑制激肽释放酶-5(KLK5)。在正常表皮中，lekti通过pH依赖的相互作用抑制KLK5。在pH为4.5-5的浅表SC中，这种复合体解离，允许KLK5蛋白水解性地激活额外的表皮激肽释放酶KLK7和KLK14以及弹性蛋白酶-2(ELA2)。这些酶能降解新生的桥粒蛋白，导致表层细胞脱落。来自人类遗传学研究、动物模型和器官型人类组织培养中lekti的siRNA敲除的最新数据表明，KLK5活性不受调控是NS的根本原因。KLK5的抑制性抗体可以通过阻断SC中的KLK5蛋白酶级联，为NS提供有效的治疗。在这个第一阶段的项目中，我们将鉴定一种抑制性的抗KLH人单抗。我们将使用器官型人体皮肤培养模型，在体外评估抑制活性。这项工作有可能导致一种新的治疗NS的方法，通过减轻新生儿危及生命的皮肤屏障缺陷，并减少成年人的皮肤刺激和炎症。这种人类抗体也可能对其他皮肤病有效，包括特应性皮炎，这些疾病涉及 激活了KLK5。

 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.