Pathogenesis and Therapy of Ichthyosis in Disorders of Lipid Metabolism

脂质代谢紊乱引起的鱼鳞病的发病机制和治疗

• 批准号: 8434177
• 负责人: Peter M Elias
• 金额: $ 31.68万
• 依托单位: NORTHERN CALIFORNIA INSTITUTE/RES/EDU
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8434177
• 关键词: Accounting; Affect; Animal Model; Appearance; Applications Grants; Biochemical Process; Biopsy; Cell membrane; Cell physiology; Cholesterol; Cholesterol Homeostasis; Clinical; Clinical Research; Coupled; Cutaneous; Defect; Disease; Distal; Distant; Doctor of Medicine; Dreams; Drug Delivery Systems; Environment; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Epidermis; Excision; Exfoliative Dermatitis; Functional disorder; Future; Gene Mutation; Ichthyoses; Inborn Genetic Diseases; Individual; Inherited; Injection of therapeutic agent; Lanosterol; Lead; Limb structure; Lipids; Lovastatin; Metabolic; Metabolic Diseases; Mutation; Pathogenesis; Pathway interactions; Patients; Permeability; Pharmaceutical Preparations; Phenotype; Production; Severities; Simvastatin; Skin; Syndrome; Therapeutic; Tissues; Toxic effect; Translating; Translations; Treatment Efficacy; Work; X-Linked Ichthyosis; base; clinical phenotype; cost; disease phenotype; effective therapy; gene therapy; improved; in vitro Model; insight; lipid disorder; lipid metabolism; novel; prevent; repaired; response; skin disorder; synthetic enzyme

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.

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。最初，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（第I组疾病），其中皮肤表型范围从重度（如CHILD综合征、纤维瘤病和SC 4 MOL缺乏症）到中度-严重（如CHH），或轻度至不明显（如SLOS和纤维瘤病）。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。