Pathogenesis and Therapy of Ichthyosis in Disorders of Lipid Metabolism

描述（由申请人提供）：目前的鱼鳞病治疗纯粹是症状性的，并且通常是不合理的;例如，当去除多余的水垢干扰了体内平衡反应，使患者能够在恶劣的陆地环境中生存时。在另一个极端，矫正基因疗法，虽然在概念上诱人，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疾病适当的动物模型中转化为易于部署的局部治疗。首先，我们将研究鱼鳞病发病机制（在患者和相关动物模型中）与遗传性、综合征性远端胆固醇代谢疾病（I组疾病），其中皮肤表型的范围可以从重度（如CHILD综合征、纤维硬结病和SC 4 MOL缺乏症）到中度-重度（如CHH）或轻度至不明显（如SLOS和桥粒甾醇病）。然后，我们将在相关的动物模型中将机理见解转化为潜在有效的疗法。这种基于发病机制的方法将扩展到其他综合征性脂质代谢障碍的患者（和动物模型）（第II组）。在动物模型中确定和优化有效疗法后，我们将为这些患者开展临床研究，作为平行赠款提案的一部分。如果成功的话，这种方法应该会在未来治疗多少鱼鳞病方面引发范式转变。最后，由于皮肤表型反映了皮外组织中也正在发生的致病机制，因此鱼鳞病的成功的基于发病机制的治疗可以指向治疗/预防这些疾病的皮外表现的类似方法。 公共卫生相关性：目前的治疗鱼鳞病的基础上，改善外观，去除多余的规模，与一个遥远的梦想，基因治疗。我们最近的工作已经阐明了导致鱼鳞病皮肤特征的细胞机制。在脂质（脂肪）代谢紊乱的情况下，基因突变导致途径终产物（例如，胆固醇）和有毒前体的积累。我们将评估这一概念是否适用于其他脂质代谢紊乱，并评估纠正这两种异常的治疗方法的疗效，从而改善临床症状。

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. PUBLIC HEALTH RELEVANCE: Current treatment of the Ichthyosis based upon improving appearance by removal of excess scale, with a distant dream of gene therapy. Our recent work has been illuminated cellular mechanisms that lead to the skin features of the Ichthyoses. In the case of disorders of lipid (fat) metabolism, genetic mutations result in both a deficiency of the pathway end-product (e.g., cholesterol) and accumulation of toxic precursors. We will assess whether this concept applies to additional lipid metabolic disorders, and assess the efficacy of therapies that correct both of these abnormalities, leading to clinical improvement.