Rare & Mosaic Disorders - Clinical Research

自然史研究 我们使用几个临床研究方案来评估多效性发育异常和节段性过度生长障碍的严重程度、畸形范围和自然病史。我们使用临床评估，包括病史和体检，影像研究包括X光、超声波和断层扫描，以及EEG、肺功能测试等，以确定功能和结构异常的特征。在选定的病例中，我们也进行外科治疗，如果它们能提供临床益处，并可以促进我们对正在研究的疾病的了解。过去研究过的一些疾病包括非综合征性多指、变形综合征、纤维脂肪过度生长综合征、黄体综合征和Lenz小眼炎综合征。我们目前的重点是Proteus综合征和相关疾病。 基因型-表型研究 遗传学研究的一个关键目标是不仅要了解哪些基因与哪些表型相关，而且要详细了解特定的变异如何与特定的表现以及这些疾病的严重程度和并发症相关。这些研究需要大量的时间和精力来吸引足够的患者。我们目前专注于节段性过度生长障碍，特别是变形杆菌综合征，并开发了一组&gt；100名患者，他们进行了详细的临床分析，并对活组织标本进行了突变检测。这里的挑战比生殖系(遗传性)疾病更大，因为除了基因、变异和遗传背景外，还必须考虑患者的嵌合体水平，这显然是一个重要的变量。 治疗性研究 变形杆菌综合征分子病因学的确定为开发这些破坏性疾病的治疗方法提供了一个令人兴奋的新机会。我们已经努力为治疗过度生长障碍的有效治疗终点开发数据。我们已经与默克公司达成了一项富有成效的合作协议，为这些试验重新调整一种肿瘤学药物的用途。我们已经进行了重要的体外工作(参见分子研究伙伴Z01)，并已完成该药物的0期剂量发现试验，已显示出良好的安全性和初步疗效(NCT02594215)。我们已经在Pharma合作伙伴的CRADA下启动了Proteus综合征的2期研究，并几乎完成了该研究的登记。

Natural history studies We operate several clinical research protocols to assess the range of severity, spectrum of malformations, and natural history of pleiotropic developmental anomalies and segmental overgrowth disorders. We use clinical evaluations that include history and physical examination, imaging studies including radiography, ultrasound, and tomography, as well as EEG, pulmonary function testing, etc. to characterize functional and structural anomalies. In selected cases we also perform surgical treatments if they offer clinical benefit and can advance our understanding of the disease under study. Some of the disorders that have studied in the past include non-syndromic polydactyly, Proteus syndrome, fibroadipose overgrowth syndrome, a progeriod syndrome, and Lenz microphthalmia syndrome. Our current focus is on Proteus syndrome and related disorders. Genotype-Phenotype studies A key objective of genetic research is to understand not only what genes are associated with what phenotypes, but to understand in detail how specific variants are correlated with specific manifestations and the severity and complications of these disorders. These studies take a great deal of time and effort to attract sufficient patients. We are currently focusing on segmental overgrowth disorders, specifically, Proteus syndrome and have developed a cohort of >100 patients with detailed clinical analysis coupled to mutation detection from biopsied specimens. The challenge here is greater than it is for germline (inherited) disorders because in addition to gene, variant, and genetic background, one must take into account the mosaicism level in the patient, which is clearly an important variable. Therapeutic Studies The identification of the molecular etiology for Proteus syndrome provided an exciting new opportunity to develop therapeutic approaches to these devastating disorders. We have undertaken efforts to develop data for valid therapeutic endpoints for therapy of overgrowth disorders. We have established a productive collaborative agreement with Merck, Inc to repurpose an oncology drug for these trials. We have performed significant in vitro work (see companion Z01 on molecular studies) and have completed a phase 0 dose finding trial for this drug which has shown good safety and preliminary efficacy (NCT02594215). We have opened a phase 2 study for Proteus syndrome under a CRADA from the Pharma partner and have nearly completed enrollment in that study.