Preclinical Development of a Novel Therapeutic Strategy for LGMD2B

LGMD2B 新型治疗策略的临床前开发

基本信息

批准号：
7895067
负责人：
TEJVIR S KHURANA
金额：
$ 15.75万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-16 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895067
关键词：
2p13 A/J Mouse Acetylcholine Affect Age-Months Biochemical Biological Assay Bromides Caenorhabditis elegans Cholinergic Receptors Chromosomes Chronic Creatine Kinase DYSF gene Data Defect Development Disease Drops Ensure Etiology FDA approved Gene Family Gene Mutation Genes Goals Health Homologous Gene In Situ Knowledge Laboratories Limb-Girdle Muscular Dystrophies Maintenance Mammals Measurement Membrane Membrane Fusion Modeling Molecular Molecular Genetics Monitor Morbidity - disease rate Muscle Muscular Dystrophies Mutation Nature Necrosis Nematoda Neuromuscular Junction Oral Oral Administration Organism Outcome Pathogenesis Patients Pharmaceutical Preparations Pharmacogenetics Phenotype Physiological Physiology Play Process Regulation Role Serum Synapses Synaptic Transmission Testing Therapeutic Therapy Clinical Trials Time United States Vesicle cost design esterase inhibitor improved in vivo member mortality mouse model neuromuscular transmission novel novel therapeutics pilot trial pre-clinical protein expression public health relevance pyridostigmine receptor recycling repaired synaptic function tool wasting

项目摘要

DESCRIPTION (provided by applicant): The long term goals of this proposal are to facilitate preclinical development of our novel therapeutic strategy for the currently incurable Limb Girdle Muscular Dystrophy Type 2B (LGMD2B). The muscular dystrophies are muscle wasting disorders with increased morbidity and mortality. LGMD2B is caused by dysferlin gene mutations leading to altered protein expression (dysferlinopathy). Deficient repair of damaged membranes via dysferlin-dependent membrane fusion has been implicated. However, lacunae exist in our knowledge of whether dysferlin regulates well-known vesicle fusion related processes (e.g. Acetylcholine Receptor (AChR) recycling & maintenance of synaptic transmission at the neuromuscular junction-NMJ). Using powerful pharmacogenetic tools available in the C. elegans model of LGMD2B, we have identified a novel role for fer-1 in the regulation of NMJ synaptic transmission (Preliminary studies). Our identification of a synaptopathic or myasthenic component has tremendous nosological and translational implications. Interestingly, Acetylcholine Esterase Inhibitors (AChEI) administration improves the survival of the A/J mouse model of LGMD2B in a small pilot trial (Preliminary Studies) and suggests the hypothesis that the NMJ deficit caused by dysferlin deficiency is amenable to treatment using AChEI as a candidate therapeutic to increase the efficiency of neuromuscular transmission and improve LGMD2B outcomes. As a specific aim we propose a well-designed, proof-of-principle study in order to complete the preliminary steps required for successful preclinical development of this candidate therapeutic and test our translational hypothesis. We will undertake a therapeutic trial where we treat 8 month old A/J mice with AChEI for 8 months. Therapeutic potential will be will be assayed using in vivo and ex vivo means to determine improvement of the dystrophic phenotype. The relevance and health relatedness of this project is that undertaking these studies we will ensure clearer understanding of the molecular and functional patho-physiology as well as facilitate preclinical development of our novel therapeutic strategy for LGMD2B. PUBLIC HEALTH RELEVANCE: The health relatedness of this project is that by completion of our aim we will ensure clearer understanding of the molecular and functional patho-physiology of limb-girdle muscular dystrophy Type 2B (LGMD2B) as well as facilitate preclinical development of our novel therapeutic strategy for LGMD2B.

描述（由申请人提供）：该提案的长期目标是为当前无法治愈的肢体腰围肌肉营养不良2B（LGMD2B）促进我们新型治疗策略的临床前发展。肌肉营养不良是肌肉浪费障碍，发病率和死亡率增加。 LGMD2B是由dysferlin基因突变引起的，导致蛋白质表达改变（dysferlinopathy）。通过dysferlin依赖性膜融合对受损的膜的修复不足已涉及。然而，我们知道dysferlin是否调节众所周知的囊泡融合相关的过程（例如，乙酰胆碱受体（ACHR）回收和维持神经肌肉连接NMJ的突触传播的回收和维持）。使用LGMD2B的秀丽隐杆线虫模型中可用的强大药物遗传学工具，我们确定了FER-1在调节NMJ突触传播（初步研究）中的新作用（初步研究）。我们对突触疗法或肌无力成分的鉴定具有巨大的性和翻译意义。有趣的是，在一项小型试验试验（初步研究）中，乙酰胆碱酯酶抑制剂（ACHEI）改善了LGMD2B的A/J小鼠模型的存活率，并表明假设由Dysferlin引起的NMJ缺乏症可以提高使用Achei anche的NE NE NEAR的治疗，以提高ACHEI的治疗方法，并提高了ACHEI的效率。结果。作为一个具体目的，我们提出了一项精心设计的原始研究，以完成成功的临床前开发所需的初步步骤，并检验我们的翻译假设。我们将进行一项治疗试验，在该试验中，我们将用ACHEI治疗8个月大的A/J小鼠8个月。将使用体内和体内手段来确定改善营养不良表型的方法，将分析治疗潜力。该项目的相关性和健康相关性是进行这些研究，我们将确保对分子和功能性病理生理学的了解更清晰，并促进我们对LGMD2B的新型治疗策略的临床前发展。公共卫生相关性：该项目的健康相关性是，通过完成我们的目标，我们将确保对肢体和肢体肌肉肌营养不良2B（LGMD2B）的分子和功能性病原体生理学有更清晰的了解，并促进我们LGMD2B的新型治疗策略的陶艺发展。