Targeted DOK7 gene therapy for Congenital Myasthenic Syndromes

项目总结 先天性肌无力综合征(CMS)是一组遗传和表型异质性， 神经肌肉传递障碍，以肌肉无力(肌无力)为特征，随着 体力消耗。DOK-7(酪氨酸激酶7下游)是神经肌肉接头的关键调节因子 (NMJ)队形。人类DOK7基因纯合性功能缺失或功能缺失突变 一种四肢带状的CMS，其特征是NMJ大约是正常大小的一半。DOK-7 CMS是个孤儿 据估计，全球有3600人受到这种疾病的影响。患有DOK-7 CMS的患者质量下降 由于运动不耐受、对间歇性呼吸支持的依赖和/或管饲导致的生命(QOL) 成年期(2/3的患者)。此外，约有一半的病人需要轮椅才能行走， 而另一半人将需要助行器。目前还没有治愈方法或标准化的治疗方法。 DOK-7 CMS。虽然CMS的形式是通过给予乙酰胆碱(AChE)抑制剂来管理的， DOK-7 CMS是难治性的，如果用AChE抑制剂治疗会恶化。症状的改善 DOK-7CMS是通过反复给予麻黄碱和沙丁胺醇，β2-肾上腺素能受体来实现的 激动剂，为一些患者提供次优的症状管理。此外，长时间暴露于 TO-β2-肾上腺素能受体可引起心动过速、心脏缺血、心力衰竭、心肌病和 炎症反应增强。Amplo生物技术公司正在开发AMP-101，这是第一种基因疗法 DOK-7 CMS的产品。治疗是基于重组腺相关病毒血清9型(AAV9)。 携带人DOK7基因的载体。在DOK-7 CMS小鼠模型上的初步结果表明，AMP-101 可以扩大NMJ，改善运动功能，延长Dok-Dok非常有限的(出生后20天)寿命- 7只CMS小鼠达到WT对照组水平。这一新产品将使目前的临床实践发生转变 从长期服用药物来缓解症状到一次性治疗，通过 单次静脉注射。该解决方案将允许医生治疗所有受影响的人群，治愈 成人疾病，以及阻止儿童疾病的进展。该SBIR快速通道项目的目标是 验证AMP-101治疗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小鼠的临床前剂量发现和安全性研究。第一阶段活动的结果将是 用于在第二阶段指导关键的DMPK/ADME和非人灵长类(NHP)毒理学研究，当 还将定义制造、质量和稳定性程序。提出的试验计划已经 已被FDA在最近的Pre-IND查询中验证，IND申请将在#年末提交 这个项目。

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.