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: 10246187
• 负责人: Penelope Hogarth
• 金额: $ 42.66万
• 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/10246187
• 关键词: Adherence; Adult; Adverse event; Affect; Anabolism; Biological; Blood - brain barrier anatomy; 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; Hallervorden-Spatz Syndrome; 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; Outcome; Outcome Measure; Pantetheine; Pantothenate kinase; Pantothenic Acid; Pathway interactions; Patients; Pattern; Pharmacodynamics; Phase; Placebos; Production; Quick Test for Liver Function; Randomized; Rare Diseases; Regimen; Research Design; Safety; Sampling; Source; Testing; Therapeutic; Time; Vitamins; Work; active method; base; cell transformation; cost; design; dietary; disability; disease-causing mutation; extracellular; family burden; improved; in vivo; mRNA Expression; medical food; mouse model; novel strategies; nutrition; open label; peripheral blood; phase 2 study; placebo group; risk minimization; safety outcomes; scale up; 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.

项目概要 我们广泛、长期的目标是为孤儿病泛酸激酶开发合理的治疗方法 相关神经变性 (PKAN)，一种维生素 B5 代谢的先天性错误，由神经元缺陷引起 编码 PANK2 的基因，这是辅酶 A 生物合成途径的第一个调控步骤，并且这样做 尽可能具有成本效益。受该疾病影响的儿童和成人会出现严重的运动 紊乱和大脑中异常铁积累的特征模式。 PKAN 影响深远 残疾和痛苦，特别是儿童，其中许多人死于该疾病的并发症 生命的第一个十年。目前还没有经过证实的疾病缓解疗法。 在这个项目中，我们将以实验室最近的工作为基础，展示令人信服的、与疾病相关的 PKAN 小鼠大脑中的分子和功能特征在两种成纤维细胞培养物中得到重现 以及人类患者的外周血中。这种生物特征在体内和体外通过 中间代谢的产物，呈剂量依赖性。 在此应用中，我们建议将这项工作扩展到临床，评估安全性、耐受性和 该产品在 2 期、随机、双盲、安慰剂对照、剂量 对患有 PKAN 的儿童和成人进行范围广泛的平行组研究。随后将进行为期 6 个月的双盲阶段 为期 18 个月的开放标签阶段。我们还将探讨应用潜在增长曲线的可行性 对纵向自然历史数据进行建模方法以捕获疾病改变效果，其目标是 为未来的研究设计提供信息。我们将采用一种新颖的方法来研究行为，旨在减少 罕见病临床研究中固有的研究参与障碍，最大限度地减少受试者的风险，并减少 家庭的负担。