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

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

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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.

项目摘要先天性肌关系综合征（CMS）是一组遗传和表型异质的，以肌肉无力（肌无力）为特征的神经肌肉传播障碍身体劳累。 DOK-7（酪氨酸激酶7的下游）是神经肌肉连接的关键调节剂（NMJ）形成。人Dok7基因基础的纯合丧失或减少功能突变 NMJ的特征是正常大小的一半的肢体类型CMS。 DOK-7 CMS是孤儿疾病估计会影响全球3600人。 DOK-7 CMS患者的质量降低生命（QOL）是由于运动性，对间歇性呼吸支持的依赖和/或管喂养成年（患者2/3）。此外，大约一半的患者需要轮椅进行移动，另一半将需要步行辅助工具。尚未为 DOK-7 CMS。虽然CMS的形式是通过乙酰胆碱（ACHE）抑制剂来管理的，但 DOK-7 CMS是难治性的，如果用ACHE抑制剂治疗，可以检测到。症状改善 DOK-7 CMS是通过复发的麻黄碱和沙丁醇β2-肾上腺素受体实现的激动剂，为某些患者提供次优症状管理。而且，长时间的暴露到β2-肾上腺素受体会引起心动过速缺血，心力衰竭，心肌病和炎症反应增加。 Amplo Biotechnology正在开发AMP-101，这是第一个基因疗法 DOK-7 CMS的产品。该处理是基于重组腺相关病毒血清型9（AAV9）的基础载有人类DOK7基因的载体。 DOK-7 CMS鼠标模型的初步结果表明AMP-101 可以增加NMJ，改善运动功能并延长Dok的寿命非常有限（出生后20天） 7 cms小鼠达到WT控件的水平。新产品将使当前的临床实践发生转变从长期给药来减轻症状到一次性治疗，通过单静脉注射。该解决方案将允许医生治疗整个受影响的人群，治愈成人疾病，并停止儿童疾病进展。这个SBIR快速轨道项目的目标是验证对DOK-7 CMS使用AMP-101的效率和安全性。 Amplo将使用I期活动进行执行在DOK-7 CMS小鼠中进行的临床前剂量调查和安全研究。第一阶段活动的结果将是用于指导非人类灵长类动物（NHP）的关键DMPK/ADME和毒理学研究，制造，质量和稳定程序也将定义。提出的实验计划已由FDA在最近的预定询问中得到了验证，并将在项目。