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.

项目摘要先天性肌关系综合征（CMS）是一组临床上相似的神经肌肉传播其潜在的基因突变不同的疾病。尽管存在某些表型变化，但CM是通常以肌肉无力（肌动症）为特征，其身体劳累恶化。缺陷胶原蛋白Q（Colq），一种负责神经肌肉连接（NMJ）的多域功能蛋白 Acheticholinestrose（ACHE）锚定和肌肉特异性激酶（MUSK）磷酸化，导致终板ACHE缺陷和COLQ CMS。 COLQ CMS是一种严重的儿科孤儿病，患病率很高在主要发达国家约有1,600人中。严重的COLQ CM会导致早期死亡并导致由于极度疲劳性而导致生活质量降低，依赖间歇性呼吸系统支撑和/或管喂养，成年初发生在2/3的患者中。无法治愈或标准化尚未针对COLQ CMS开发治疗。虽然某些CMS类型是通过管理管理的在ACHE抑制剂中，COLQ CMS是难治性的，如果用ACHE抑制剂治疗，可以检测到。最好的护理涉及2-肾上腺素受体激动剂的长期给药，它仅提供适中有症状的改善。 Amplo Biotechnology正在开发CMS的治疗方法，试图简化通过应用平台方法来测试新的腺相关病毒（AAV）的过程相同的基因输送系统和制造方法，随后的指示可以由改变动物模型和传递的转换。这种方法可以节省时间，金钱并将最终允许在传统药物的情况下满足较小的患者人群的未满足需求开发投资成本在商业上是不可行的。 AMP-2011是第一个用于 COLQ CMS，基于携带人类COLQ基因的AAV8矢量。提出的开发途径基于监管（预先印度，前CTA）和科学建议（TACT，treat-nmd）提供了 Amplo正在为DOK-7 CMS开发的密切相关的基因疗法（Fast-Track SBIR最近授予）。 colq CMS鼠标模型的初步结果表明，aav8-colq的内部注入能够纠正Colq - / - 小鼠模型中AMP-201的病理迹象，该模型概括了表型 COLQ CMS。 AMP-2011将使当前的临床实践从长期给药到药物的临床实践转变为减轻一次性治疗的症状，使医生可以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STTR快速轨道项目的目标是验证COLQ CMS使用AMP-201的效率和安全性。 Amplo将使用I期活动进行执行在COLQ - / - 小鼠中进行的临床前剂量调查和效率研究。第一阶段活动的结果将被使用在非人类灵长类动物（NHP）中的小鼠和关键DMPK/ADME和毒理学的直接毒性研究（NHP）第二阶段。制造，质量和稳定程序也将定义。