Development of a splicing modulator compound for familial dysautonomia

开发用于家族性自主神经功能障碍的剪接调节剂化合物

• 批准号: 10680719
• 负责人: Susan A Slaugenhaupt
• 金额: $ 21.14万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10680719
• 关键词: Affect; Age; Binding Proteins; Brain; Cells; Central Nervous System; Clinic; Clinical; Clinical Trials; Communication; Complex; Congenital Neuropathy; Contractor; Cytokinins; Data; Defect; Development; Disease; Drug Interactions; Drug Screening; Familial Dysautonomia; Formulation; Funding; Gait; Gait Ataxia; Goals; Grant; Hand; Hereditary Sensory and Autonomic Neuropathies; Impaired cognition; In Vitro; Individual; Kinetins; Laboratories; Lead; Life; Messenger RNA; Modification; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Nervous System; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neurons; Pain; Patients; Perception; Peripheral Nervous System; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phenotype; Plants; Polymorph; Preparation; Program Development; Proteins; RNA Splicing; Retinal Degeneration; Running; Schedule; Scheme; Sensory; Severity of illness; Sodium Chloride; Suspensions; Tablets; Temperature; Therapeutic; Time; Tissues; Translating; Tween 80; United States National Institutes of Health; Work; autonomic neuropathy; clinical development; cost; disease phenotype; exon skipping; first-in-human; humanized mouse; improved; in vivo; innovation; meetings; mouse model; nervous system disorder; neuronal survival; novel therapeutics; patient population; patient retention; phase I trial; pre-clinical; prevent; programs; protein complex; scale up; screening; sensory neuropathy; small molecule; stretch reflex; therapy development; translational medicine

Familial dysautonomia (FD), also known as HSAN type III or Riley-Day syndrome, is a rare, fatal, congenital sensory and autonomic neuropathy caused by a “leaky” RNA splicing defect that results in reduced levels of ELP1 protein mainly in the nervous system. Patients with FD have a complex neurological phenotype with diminished pain and temperature perception, decreased or absent myotatic reflexes, proprioceptive gait ataxia, and progressive retinal degeneration. After identifying kinetin as a small molecule able to correct the ELP1 splicing defect, we worked as part of the NIH Blueprint Neurotherapeutics Network to optimize the potency and efficacy of kinetin and create a new class of splicing modulator compounds (SMCs). In 2015, we partnered with PTC Therapeutics to further develop these compounds with the goal of bringing a new drug to FD patients. After four years of highly collaborative work, PTC Therapeutics canceled the FD program in late 2019 due to budgetary constraints associated with the development of a drug for such a rare patient population. The goal of this proposal is to complete the IND-enabling studies for our lead compound, PTC680, and to conduct a Phase I clinical trial taking full advantage of the expertise and guidance of BPN consultants and contractors. PTC680 is an excellent development candidate: 1) It is a potent modulator of ELP1 splicing both in vitro and in vivo and, importantly, leads to an increase in functional ELP1 protein in mice in all tissues, including brain, 2) Discovery stage projects are complete and a reasonable synthesis scheme has been developed, and 3) It has a good ADME profile, limited potential for drug-drug interactions and similar protein binding across species. Therefore, preclinical data should promptly translate to the clinic. The proposed project will enter at the Development stage and will use the expertise of NIH contractors to move PTC680 to the clinic. In the UG3 phase, we will perform the preparatory work for the IND-enabling studies including further optimization of the synthesis strategy to produce enough material for the proposed studies, and determine a suitable formulation. During the development phase (UH3) will use the BPN CROs to conduct the IND-enabling studies and the Phase I clinical trial in healthy individuals. During this phase of the program, we will be responsible for overall project management together with the CDT, assembly, and submission of the IND application, and all communications with the FDA. We are confident that with the support of the Blueprint network, we will be successful in our quest to finally bring a disease-modifying therapy to FD patients.

家族性自主神经障碍(FD)，也被称为HSAN III型或Riley-Day综合征，是一种罕见的、致命的先天性 由“泄漏”的RNA剪接缺陷引起的感觉和自主神经病变，导致水平降低 ELP1蛋白主要存在于神经系统中。FD患者具有复杂的神经学表型， 疼痛和温度感觉减弱，肌张力反射减弱或消失，本体感觉步态共济失调， 和进行性视网膜变性。在确认激动素是一种能够纠正ELP1的小分子后 剪接缺陷，我们作为NIH蓝图神经治疗网络的一部分工作，以优化效力和 激动素的功效，并创造了一类新的剪接调节剂化合物(SMC)。2015年，我们与 PTC治疗公司进一步开发这些化合物，目标是为FD患者带来一种新药。之后 经过四年的高度协作，PTC Treeutics在2019年底因预算原因取消了FD计划 与为如此罕见的患者群体开发药物相关的限制。这样做的目的是 提案是完成我们的先导化合物PTC680的IND使能研究，并进行第一阶段 临床试验充分利用BPN顾问和承包商的专业知识和指导。PTC680是 一个极好的候选开发：1)它是ELP1在体外和体内剪接的有效调节剂， 重要的是，导致小鼠所有组织中功能性ELP1蛋白的增加，包括大脑，2)发现 阶段性项目齐全，制定了合理的综合方案；3)综合效果好 ADME概况，药物-药物相互作用的有限潜力和跨物种的类似蛋白质结合。因此， 临床前数据应迅速转化为临床数据。拟建项目将进入开发阶段 并将利用NIH承包商的专业知识将PTC680转移到诊所。在UG3阶段，我们将表演 促进可持续发展研究的筹备工作，包括进一步优化综合战略，以 为拟议的研究提供足够的材料，并确定合适的配方。在开发过程中 阶段(UH3)将使用BPN CRO在健康人群中进行IND使能研究和I阶段临床试验 个人。在项目的这一阶段，我们将共同负责项目的整体管理 负责IND申请的CDT、组装和提交，以及与FDA的所有沟通。我们是 相信在蓝图网络的支持下，我们将成功地寻求最终带来 对功能性消化不良患者的疾病修正疗法。