Targeted DOK7 gene therapy for Congenital Myasthenic Syndromes

先天性肌无力综合征的靶向 DOK7 基因治疗

基本信息

批准号：
10705846
负责人：
Patricio Sepulveda
金额：
$ 14.41万
依托单位：
AMPLO BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10705846
关键词：
Acetylcholine Acetylcholinesterase Inhibitors Adrenergic Agonists Adult Advanced Development Affect Albuterol Amyotrophic Lateral Sclerosis Biodistribution Biological Assay Biological Products Biotechnology Birth Breathing Cardiomyopathies Child Childhood Choking Chronic Clinic Clinical Clinical Trials Collaborations Congenital Myasthenic Syndromes Cytomegalovirus Defect Dependence Deterioration Disease Disease Management Disease Progression Dose Engineering Ensure Enteral Feeding Ephedrine Evaluation Exertion Exposure to Genes Goals Health Heart failure Human Inflammatory Response Inherited Intervention Limb structure Longevity Mus Muscle Weakness Muscular Dystrophies Mutation Myasthenia Myocardial Ischemia National Institute of Neurological Disorders and Stroke Neurodegenerative Disorders Neurology Neuromuscular Diseases Neuromuscular Junction Neuromuscular Junction Diseases Outcome Patients Pattern Persons Pharmaceutical Preparations Phase Phenotype Physicians Population Preparation Procedures Production Protein Tyrosine Kinase Quality of life Rare Diseases Recombinant adeno-associated virus (rAAV)Recurrence Refractory Respiratory Insufficiency Running Safety Serotyping Signal Transduction Small Business Innovation Research Grant Spinal Muscular Atrophy Standardization Synapses Syndrome Tachycardia Testing Time Tokyo Toxic effect Toxicology Tracheostomy procedure Universities Validation Viral Vector Walking Western Blotting Wheelchairs assay development beta-2 Adrenergic Receptors clinical development clinical practice design disease-causing mutation efficacy evaluation efficacy study efficacy validation exercise intolerance experimental study feeding forging gene therapy improved inhibitor insight intravenous administration intravenous injection manufacture motor function improvement mouse model nonhuman primate novel pharmacokinetics and pharmacodynamics pharmacologic pre-clinical preclinical development preclinical efficacy preclinical study programs recruit reduce symptoms respiratory response safety study sarcopenia scoliosis spelling symptom management transmission process vector

项目摘要

PROJECT SUMMARY Congenital Myasthenic Syndromes (CMS) are a group of genetically and phenotypically heterogeneous, neuromuscular transmission disorders characterized by muscle weakness (myasthenia) that worsens with physical exertion. DoK-7 (Downstream of tyrosine kinase 7) is a key regulator of neuromuscular junction (NMJ) formation. Homozygous loss-of or reduction of-function mutations in the human DOK7 gene underlie a limb-girdle type of CMS characterized by NMJs that are about half the normal size. DoK-7 CMS is an orphan disease estimated to affect 3,600 people worldwide. Patients with DoK-7 CMS have a decreased Quality of Life (QoL) due to exercise intolerance, dependency on intermittent respiratory support, and/or tube feeding by adulthood (2/3 of the patients). Moreover, about half of the patients will need a wheelchair for ambulation, and the other half will require walking aids. No cure nor standardized treatment has been yet developed for DoK-7 CMS. While forms of CMS are managed through the administration of acetylcholine (AChE) inhibitors, DoK-7 CMS is refractory and can deteriorate if treated with AChE inhibitors. Symptoms ameliorations for DoK-7 CMS is achieved by recurrent administration of Ephedrine and Albuterol, β2-adrenergic receptor agonists, which provide suboptimal symptom management for some patients. Moreover, prolonged exposure to β2-adrenergic receptor can cause tachycardia cardiac ischemia, heart failure, cardiomyopathy, and increased inflammatory response. Amplo Biotechnology is developing AMP-101, the first gene therapy product for DoK-7 CMS. The treatment is based on a recombinant adeno-associated virus serotype 9 (AAV9) vector carrying the human DOK7 gene. Preliminary results in a DoK-7 CMS mouse model show that AMP-101 can enlarge NMJs, improve motor function, and extend the very limited (20 days after birth) life span of DoK- 7 CMS mice to the level of WT controls. The new product will enable a shift in the current clinical practice from chronic administration of drugs to alleviate symptoms to a one-off treatment, administered through a single intravenous injection. The solution will allow physicians to treat the entire affected population, curing adult disease, and stopping disease progression in children. The goal of this SBIR Fast-Track project is to validate the efficacy and safety of using AMP-101 for DoK-7 CMS. Amplo will use Phase I activities to perform a pre-clinical dose-finding and safety study in DoK-7 CMS mice. The outcome of Phase I activities will be used to direct pivotal DMPK/ADME and toxicology studies in non-human primates (NHP) in Phase II, when manufacturing, quality, and stability procedures will also be defined. The experimental plan proposed has been validated by the FDA in a recent pre-IND query and an IND application will be submitted at the end of the project.

项目概要先天性肌无力综合征 (CMS) 是一组遗传和表型异质性、以肌肉无力（肌无力）为特征的神经肌肉传递障碍，病情恶化 DoK-7（酪氨酸激酶 7 的下游）是神经肌肉接头的关键调节因子。 (NMJ) 形成是人类 DOK7 基因纯合性丧失或功能减少突变的基础。肢带型 CMS 的特征是 NMJ 大小约为正常大小的一半，DoK-7 CMS 是一种孤儿。据估计，DoK-7 CMS 患者的疾病影响了全球 3,600 人的质量下降。由于运动不耐受、依赖间歇性呼吸支持和/或管饲而导致的生活质量 (QoL) 成年后（2/3的患者），大约一半的患者需要轮椅行走，另一半则需要助行器，目前尚未开发出治愈方法或标准化治疗方法。 DoK-7 CMS。虽然 CMS 的形式是通过施用乙酰胆碱 (AChE) 抑制剂来管理的， DoK-7 CMS 是难治性的，如果用 AChE 抑制剂治疗症状会恶化。 DoK-7 CMS 通过反复施用麻黄碱和沙丁胺醇（β2-肾上腺素能受体）来实现激动剂，这对某些患者的症状管理效果不佳，而且长时间暴露。 β2-肾上腺素能受体可引起心动过速、心肌缺血、心力衰竭、心肌病等 Amplo Biotechnology 正在开发第一种基因疗法 AMP-101。用于 DoK-7 CMS 的产品该治疗基于重组腺相关病毒血清型 9 (AAV9)。携带人类 DOK7 基因的载体在 DoK-7 CMS 小鼠模型中的初步结果表明 AMP-101 可以扩大 NMJ，改善运动功能，并延长 DoK 非常有限的寿命（出生后 20 天） 7 CMS 小鼠达到 WT 对照水平，新产品将使当前临床实践发生转变。从长期服用药物缓解症状到通过特定途径进行的一次性治疗该解决方案将使医生能够治疗所有受影响的人群并治愈。成人疾病，并阻止儿童疾病进展该 SBIR 快速通道项目的目标是验证使用 AMP-101 用于 DoK-7 CMS 的有效性和安全性 Amplo 将使用第一阶段活动来执行。 DoK-7 CMS 小鼠的临床前剂量探索和安全性研究 I 期活动的结果将是。用于指导第二阶段非人类灵长类动物 (NHP) 的关键 DMPK/ADME 和毒理学研究，当还将定义所提出的实验计划。已在最近的 IND 前查询中得到 FDA 的验证，并将在年底提交 IND 申请该项目。