Pathogenesis and Therapy of Ichthyosis in Disorders of Lipid Metabolism

描述(申请人提供)：目前对鱼鳞病的治疗纯粹是有症状的，而且往往是不合理的；例如，当去除多余的鳞片干扰了允许患者在恶劣的陆地环境中生存的体内平衡反应时。在另一个极端，纠正性基因疗法虽然在概念上很诱人，但仍然是一个遥远的梦想，有许多潜在的陷阱。我们的方法将首先确定患者的致病机制，然后评估这些新信息是否可以在适合疾病的动物模型中转化为易于部署的局部治疗。首先，我们将研究鱼鳞病的发病机制(在患者和相关动物模型中)，并伴有遗传性、综合征性的远端胆固醇代谢紊乱(I组障碍)，其中皮肤表型从重度(如儿童综合征、肥胖症和SC4MOL缺乏症)到中-重度(如CHH)，或轻度到不明显(如SLOS和促纤维激素缺乏)。然后，我们将在相关动物模型中将机械性见解转化为潜在有效的治疗方法。然后，这种基于发病机制的方法将扩展到其他脂代谢综合征障碍的患者(和动物模型)(第二组)。在动物模型中确定和优化有效的治疗方法后，我们将启动针对这些患者的临床研究，作为平行拨款提案的一部分。如果成功，这种方法应该会引发未来治疗多少鱼鳞病的范式转变。最后，由于皮肤表型反映了皮外组织中也在进行的致病机制，成功的基于发病机制的鱼鳞病治疗可能指向治疗/预防这些疾病的皮外表现的类似方法。

DESCRIPTION (provided by applicant): Current therapy of the Ichthyoses is purely symptomatic, and often irrational; e.g., when removal of excess scale interferes with homeostatic responses that allow patients to survive in a harsh, terrestrial environment. At the other extreme, corrective gene therapy, though seductive in concept, remains a distant dream, with many potential pitfalls. Our approach will be first, to identify pathogenic mechanisms in patients, and then to assess whether this new information can be translated into readily-deployable, topical therapy in disease-appropriate animal models. Initially, we will study Ichthyosis pathogenesis (in patients and relevant animal models) with inherited, syndromic disorders of distal cholesterol metabolism (Group I disorders) where the cutaneous phenotype can range from severe (as in CHILD syndrome, lathosterolosis, and SC4MOL deficiency), to moderately-severe (as in CHH), or mild-to-inapparent (as in SLOS and desmosterolosis). Then, we will translate mechanistic insights into potentially-effective therapies in relevant animal models. This pathogenesis-based approach then will be extended to patients (and animal models) of other syndromic disorders of lipid metabolism (Group II). Following identification and optimization of effective therapy in the animal models, we will launch clinical studies for these patients, as part of a parallel grant proposal. If successful, this approach should initiate a paradigm shift in how many of the Ichthyoses will be treated in the future. Finally, since the cutaneous phenotype reflects pathogenic mechanisms that also are on-going in extracutaneous tissues, successful pathogenesis-based therapy for the Ichthyoses could point to comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.