Pathogenesis and Therapy of Ichthyosis in Disorders of Lipid Metabolism

目前鱼鳞病的治疗方法，包括脂肪合成型、常染色体隐性遗传性先天性鱼鳞病 (ARCI)，在很大程度上是有症状的，而且通常是不合理的；例如，当清除多余的鳞片干扰 使患者能够在恶劣的地面环境中生存的动态平衡反应。在另一个极端， 纠正性基因治疗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。 我们提出的新方法首先是确定急性心肌梗死患者的致病机制，使用 来自患者和动物模型的活检，以及ARCI的器官类型模型(HEES)，制备自 患者成纤维细胞或角质形成细胞系，或通过CRISPR/CAS9技术从正常成纤维细胞中分离出来。 利用超微结构、脂质生化和rna-seq技术，我们将评估细胞和遗传学。 这些疾病的基础，并确定说明患者存活的代偿机制。然后我们就会 评估这些新信息是否可以转化为易于部署的局部治疗方法 它们在ARCI Hees和适合疾病的动物模型中进行了初步优化。在确认身份和 优化动物模型的有效治疗，我们将启动针对这些患者的临床研究， 得到一项平行赠款提案的支持。如果成功，这种方法应该会引发一场范式转变， 的鱼鳞病将在未来得到治疗。最后，由于皮肤表型反映了病原体 在以皮外疾病为表现的综合征障碍中也正在进行的机制， 对于这些ARCI，成功的基于发病机制的治疗也可以确定类似的治疗方法 治疗/预防这些疾病的皮外表现。

Current therapy of the ichthyoses, including the lipid synthetic, autosomal recessive congenital ichthyoses (ARCI), is largely 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 proposed new approach has been first, to identify pathogenic mechanisms in ARCI patients, using biopsies from patients and animal models, as well as organotypic models (HEEs) of the ARCI, prepared from either patient fibroblast or keratinocyte cell lines, or from normal fibroblasts by CRISPR/Cas 9 technology. Using ultrastructural, lipid biochemical, and RNA-seq technology, we will assess both the cellular and genetic basis for these disorders, and identify compensatory mechanisms that account for patient survival. We then will assess whether this new information can translate into readily-deployable, topical therapies for patients after their initial optimization in ARCI HEEs, and in disease-appropriate animal models. Following identification and optimization of effective therapy in the animal models, we will initiate clinical studies for these patients, supported by 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 syndromic disorders with extracutaneous disease manifestations, successful pathogenesis-based therapy for these ARCI could also identify comparable approaches to treat/prevent the extracutaneous manifestations of these disorders.