Targeted ColQ gene therapy for Congenital Myasthenic Syndromes

先天性肌无力综合征的靶向 ColQ 基因治疗

基本信息

批准号：
10602652
负责人：
RICARDO Anibal MASELLI
金额：
$ 49.31万
依托单位：
AMPLO BIOTECHNOLOGY, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10602652
关键词：
Acetylcholinesterase Acetylcholinesterase Inhibitors Address Adrenergic Agonists Adult Affect Albuterol Animal Model Award Biological Assay Biotechnology Cardiomyopathies Caring Cessation of life Child Childhood Choking Chronic Circulation Clinical Collaborations Collagen Congenital Myasthenic Syndromes DNA Sequence Alteration Defect Dependence Dependovirus Deterioration Developed Countries Development Disease Disease Management Disease Progression Dose Eligibility Determination Ensure Enteral Feeding Ephedrine Exertion Exposure to Goals Health Heart failure Hemophilia A Human Inflammatory Response Inherited Intervention Intramuscular Injections Intravenous Investments Lead Left Limb structure Limb-Girdle Muscular Dystrophies Liver MUSK gene Methods Morphology Motor Mus Muscle Muscle Weakness Myasthenia Myocardial Ischemia Neuromuscular Diseases Neuromuscular Junction Neuromuscular Junction Diseases Ontario Outcome Pathologic Pathway interactions Patients Pattern Pediatric Hospitals Persons Pharmaceutical Preparations Phase Phenotype Phosphorylation Physicians Population Preparation Prevalence Procedures Process Production Proteins Quality of life Rare Diseases Refractory Respiratory Failure Respiratory Insufficiency Safety Signal Transduction Small Business Innovation Research Grant Small Business Technology Transfer Research Standardization Symptoms Synapses Tachycardia Testing Therapeutic Time Toxic effect Toxicology Transgenes United States National Institutes of Health Universities Validation Variant Vocal Cord Paralysis assay development beta-2 Adrenergic Receptors clinical development clinical practice cost design disease-causing mutation drug development efficacy study efficacy validation emerging adult gene delivery system gene therapy improved inhibitor insight intravenous administration intravenous injection manufacture mouse model neuromuscular transmission nonhuman primate patient population pre-clinical preclinical development preclinical efficacy preclinical study programs promoter recruit reduce symptoms respiratory response scoliosis side effect spelling symptom management symptomatic improvement therapy development tibialis anterior muscle transmission process vector vif Genes

项目摘要

PROJECT SUMMARY Congenital Myasthenic Syndromes (CMS) are a group of clinically similar neuromuscular transmission disorders that differ in their underlying genetic mutation. While some phenotypical variation exists, CMS are commonly characterized by muscle weakness (myasthenia) that worsens with physical exertion. Defects in Collagen Q (ColQ), a multidomain functional protein of the Neuro Muscular Junction (NMJ) responsible for AChEticholinesterase (AChE) anchoring and Muscle specific Kinase (MusK) phosphorylation, lead to endplate AChE deficiency and ColQ CMS. ColQ CMS is a severe, pediatric orphan disease with a prevalence of approximately 1,600 people in the major developed countries. Severe ColQ CMS can result in early death and causes decreased Quality of Life due to extreme fatigability, dependency on intermittent respiratory support, and/or tube feeding, which occurs in 2/3 of patients by early adulthood. No cure nor standardized treatment has been yet developed for ColQ CMS. While some CMS subtypes are managed via administration of AChE inhibitors, ColQ CMS is refractory and can deteriorate if treated with AChE inhibitors. Best available care involves chronic administration of ?2-adrenergic receptor agonists, which only provide modest symptomatic improvements. Amplo Biotechnology is developing treatments for CMS, seeking to streamline the process of testing new adeno-associated virus (AAV) by applying a platform approach whereas, by using the same gene delivery system and manufacturing methods, subsequent indications can be targeted by changing the animal model and the transgene delivered. This approach will save time, money and will ultimately allow to address the unmet needs of smaller patients’ populations where traditional drug development investments cost are commercially unviable. AMP-201, is the first gene therapy product for ColQ CMS, based on an AAV8 vector carrying the human ColQ gene. The development pathway presented has been based on regulatory (pre-IND, pre-CTA) and scientific advice (TACT, Treat-NMD) provided for a closely related gene therapy that Amplo is developing for Dok-7 CMS (Fast-track SBIR recently awarded). Preliminary results in a ColQ CMS mouse model show that intra-venous injection of a AAV8-COLQ is able to correct the pathological signs of AMP-201 in the ColQ -/- mice model which recapitulates the phenotype of ColQ CMS. AMP-201 will enable a shift in the current clinical practice from chronic administration of drugs to alleviate symptoms to a one-off treatment allowing physicians to treat the entire affected population, curing adult disease, and stopping disease progression in children. The goal of this STTR Fast-Track project is to validate the efficacy and safety of using AMP-201 for ColQ CMS. Amplo will use Phase I activities to perform a pre-clinical dose-finding and efficacy study in ColQ -/- mice. The outcome of Phase I activities will be used to direct toxicity studies in mice and pivotal DMPK/ADME and toxicology in non-human primates (NHP) in Phase II. Manufacturing, quality, and stability procedures will also be defined.

项目概要先天性肌无力综合症（CMS）是一组临床上相似的神经肌肉传导综合征其潜在基因突变不同的疾病虽然存在一些表型变异，但 CMS 是不同的。通常以肌肉无力（肌无力）为特征，并随着体力消耗而恶化。胶原蛋白 Q (ColQ)，神经肌肉接头 (NMJ) 的一种多域功能蛋白，负责乙酰胆碱酯酶 (AChE) 锚定和肌肉特异性激酶 (MusK) 磷酸化，导致终板乙酰胆碱酯酶缺乏症和 ColQ CMS ColQ CMS 是一种严重的儿童孤儿病，普遍存在。在主要发达国家，大约有 1,600 人患有严重 ColQ CMS 可能导致过早死亡。由于极度疲劳、依赖间歇性呼吸，导致生活质量下降支持和/或管饲，2/3 的患者在成年早期会出现这种情况，无法治愈也无法标准化。 ColQ CMS 的治疗方法尚未开发，而某些 CMS 亚型是通过管理进行管理的。对于 AChE 抑制剂，ColQ CMS 是难治性的，如果使用 AChE 抑制剂治疗，可能会恶化。护理涉及长期给予β2-肾上腺素能受体激动剂，其仅提供适度的作用 Amplo Biotechnology 正在开发 CMS 的治疗方法，寻求简化。通过应用平台方法测试新的腺相关病毒（AAV）的过程，而通过使用相同的基因传递系统和制造方法，后续的适应症可以通过改变动物模型和传递的转基因将节省时间、金钱和意志。最终能够解决传统药物无法满足的较小患者群体的未满足需求 AMP-201的开发投资成本在商业上不可行，是第一个基因治疗产品。 ColQ CMS，基于携带人类 ColQ 基因的 AAV8 载体。已基于监管（IND 前、CTA 前）和科学建议（TACT、Treat-NMD）提供 Amplo 正在为 Dok-7 CMS 开发密切相关的基因疗法（最近荣获快速通道 SBIR）。 ColQ CMS 小鼠模型的初步结果表明，静脉内注射 AAV8-COLQ 能够纠正 ColQ -/- 小鼠模型中 AMP-201 的病理体征，该模型概括了表型 ColQ CMS。AMP-201 将使当前的临床实践从长期给药转向通过一次性治疗缓解症状，使医生能够治疗所有受影响的人群，治愈 STTR 快速通道项目的目标是：验证使用 AMP-201 用于 ColQ CMS 的有效性和安全性 Amplo 将使用 I 期活动来进行。 ColQ -/- 小鼠的临床前剂量探索和功效研究将使用 I 期活动的结果。指导小鼠毒性研究以及非人类灵长类动物 (NHP) 的关键 DMPK/ADME 和毒理学研究第二阶段还将定义制造、质量和稳定性程序。