A phase 2 study of a vitamin metabolite for PKAN

PKAN 维生素代谢物的 2 期研究

• 批准号: 10683049
• 负责人: Penelope Hogarth
• 金额: $ 42.52万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10683049
• 关键词: 4' -phosphopantetheine; Adherence; Adult; Adverse event; Affect; Anabolism; Biological; Brain; Categories; Cell Culture Techniques; Characteristics; Child; Clinic; Clinical Research; Coenzyme A; Collaborations; Data; Defect; Development; Disease; Disease Management; Dose; Double-Blind Method; Down-Regulation; Enzymes; Feedback; Fibroblasts; Food; Food Safety; Formulation; Future; Genes; Goals; Growth; Hereditary Disease; Human; In Vitro; Inborn Errors of Metabolism; Intervention; Iron; Knockout Mice; Laboratories; Life; Measurable; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; Molecular Profiling; Movement Disorders; Mus; Mutation; Natural History; Neurologic; Nutritional; Oral Administration; Outcome; Outcome Measure; Pantothenate kinase; Pantothenate kinase-associated neurodegeneration; Pantothenic Acid; Pathway interactions; Patients; Pattern; Pharmacodynamics; Phase; Phosphorylation; Placebo Control; Placebos; Randomized; Rare Diseases; Regimen; Research Design; Safety; Sampling; Source; Testing; Therapeutic; Time; Vitamins; Work; active method; blood-brain barrier crossing; cell transformation; cost; design; dietary; disability; disease-causing mutation; extracellular; family burden; improved; in vivo; mRNA Expression; manufacturing scale-up; medical food; mouse model; novel strategies; nutrition; open label; peripheral blood; phase 2 study; placebo group; risk minimization; safety outcomes; vitamin metabolism

Project Summary Our broad, long-term goal is to develop rational therapeutics for the orphan disease pantothenate kinase- associated neurodegeneration (PKAN), an inborn error of vitamin B5 metabolism that is caused by defects in the gene that encodes PANK2, the first regulatory step in the coenzyme A biosynthetic pathway, and to do so as cost-effectively as possible. Children and adults affected by the disease develop a severe movement disorder and a characteristic pattern of abnormal iron accumulation in the brain. PKAN causes profound disability and suffering, especially in children, many of whom succumb to complications of the disease in the first decade of life. No proven disease-modifying therapy is currently available. In this project, we will build on recent work from the laboratory demonstrating a compelling, disease-relevant molecular and functional signature in the PKAN mouse brain that is recapitulated in both fibroblast cell cultures and in peripheral blood from human patients. This biological signature is ameliorated in vivo and in vitro by a product of intermediary metabolism in a dose-dependent fashion. In this application, we propose to extend this work to the clinic, evaluating the safety, tolerability and pharmacodynamic profile of the product in a phase 2, randomized, double-blind, placebo-controlled, dose- ranging, parallel-group study in children and adults with PKAN. A 6-month double-blind phase will be followed by an 18-month open-label phase. We will also explore the feasibility of applying a latent growth curve modeling approach to longitudinal natural history data to capture a disease modifying effect, with the goal of informing future study design. We will employ a novel approach to study conduct that is designed to reduce the barriers to study participation inherent in rare disease clinical research, minimize risks to subjects, and lessen the burden on families.

项目摘要 我们广泛的长期目标是开发针对孤儿疾病泛素激酶的合理治疗方法。 相关神经变性（PKAN），这是维生素B5代谢的先天误差，是由缺陷引起的 编码PANK2的基因，这是辅酶A生物合成途径中的第一个调节步骤，并这样做 尽可能成本效率。受该疾病影响的儿童和成人发生了严重运动 脑部异常铁积聚的疾病和特征模式。 PKAN引起了深刻的影响 残疾和痛苦，尤其是在儿童中，其中许多人屈服于该疾病并发症 生命的第一十年。目前尚无证实的疾病改良疗法。 在这个项目中，我们将以实验室的最新工作为基础，展示了引人入胜的，与疾病相关的工作 PKAN小鼠大脑中的分子和功能特征，在两个成纤维细胞培养物中都概括 以及人类患者的外周血。该生物学特征在体内和体外得到改善 中介代谢的产物以剂量依赖性方式。 在此应用中，我们建议将这项工作扩展到诊所，评估安全性，耐受性和 产品在2阶段中的药效学谱，随机，双盲，安慰剂对照，剂量 - 在儿童和成人PKAN的范围内，平行组研究。将遵循6个月的双盲阶段 按18个月的开放标签阶段。我们还将探索应用潜在生长曲线的可行性 纵向自然历史数据的建模方法以捕获疾病的修饰作用，目的是 告知未来的研究设计。我们将采用一种新颖的方法来研究行为，旨在减少 研究罕见疾病临床研究固有的研究参与的障碍，最大程度地降低受试者的风险并减少 家庭负担。