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

• 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
• 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

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.

项目总结 先天性肌无力综合征(CMS)是一组临床相似的神经肌肉传递 在潜在基因突变上不同的疾病。虽然存在一些表型变异，但不育系 通常以肌肉无力(肌无力)为特征，随着体力的消耗而恶化。中的缺陷 胶原蛋白Q(ColQ)是神经肌肉接头(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AChE缺乏和ColQ CMS。ColQ CMS是一种严重的儿科孤儿疾病， 主要发达国家约有1600人。严重的ColQ CMS可导致过早死亡 并因极度疲劳、对间歇性呼吸的依赖而导致生活质量下降 支持，和/或管喂养，这发生在2/3的患者在成年早期。没有治愈方法，也没有标准化 ColQ CMS的治疗方法尚未开发出来。而一些CMS子类型通过管理进行管理 在AChE抑制剂中，ColQ CMS是难治性的，如果与AChE抑制剂一起治疗，可能会恶化。最好的服务 CARE包括长期使用β2-肾上腺素能受体激动剂，这些药物只能提供适量的 症状改善。Amplo Biotech正在开发CMS的治疗方法，寻求简化 应用平台法测试新腺相关病毒(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 改变动物模型和提供的转基因。这种方法将节省时间、金钱和意志 最终允许满足较小患者群体的未得到满足的需求，其中传统药物 开发投资成本在商业上是不可行的。AMP-201，是首个针对 ColQ CMS，基于携带人ColQ基因的AAV8载体。提出了发展的路径。 以法规(Pre-IND、Pre-CTA)和科学建议(Tact、Treat-NMD)为基础 Amplo正在为DOK-7 CMS开发密切相关的基因疗法(Fast-Track SBIR最近获奖)。 在ColQ CMS小鼠模型中的初步结果表明，静脉注射AAV8-COLQ能够 纠正AMP-201在ColQ-/-小鼠模型中的病理征象，概括了 ColQ CMS。AMP-201将使目前的临床实践从长期给药转变为 将症状缓解为一次性治疗，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。STTR快速通道项目的目标是 验证使用AMP-201治疗ColQ CMS的有效性和安全性。Amplo将使用第一阶段活动来执行 ColQ-/-小鼠的临床前剂量发现和疗效研究。将使用第一阶段活动的结果 指导小鼠毒性研究和关键的DMPK/ADME以及非人类灵长类动物(NHP)的毒理学 第二阶段。还将定义制造、质量和稳定性程序。