Novel Adjunctive Therapies for Pompe Disease

庞贝病的新型辅助疗法

基本信息

批准号：
10545059
负责人：
Angela L. Roger
金额：
$ 10.57万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10545059
关键词：
Acute Address Affect Architecture Automobile Driving Autophagocytosis Autophagosome Blood Brain Breathing Cardiac Cell Therapy Childhood Clinical Clinical Treatment Clinical Trials Collaborations Complex Disease Distress Environment Enzymes FDA approved FRAP1 gene Foundations Functional disorder Future Gene Delivery Genes Glucan 1,4-alpha-Glucosidase Glycogen Glycogen Storage Disease Glycogen storage disease type II Goals Health Heart Heart Hypertrophy Human Hypoxia Immune response Immunohistochemistry Immunosuppressive Agents Infant Intervention Knowledge Lead Location Lysosomes Mentors Metabolic Methods Molecular Motor Motor Neurons Mus Muscle Muscle Weakness Muscle function Myocardium Nerve Neurobiology Neuromuscular Diseases Neuronal Plasticity Nutrient Organelles Output Pathology Pathway interactions Patient Care Patients Phase Process Proteins Proteomics Recombinant adeno-associated virus (rAAV)Recombinants Recycling Research Research Personnel Respiration Respiratory Failure Respiratory Muscles Respiratory Therapy Respiratory distress Respiratory physiology Scientist Secondary to Sirolimus Skeletal Muscle Testing Therapeutic Translating Universities Viral Genes Whole Body Plethysmography Work adeno-associated viral vector blood-brain barrier crossing career clinical care disease-causing mutation enzyme deficiency enzyme replacement therapy experience experimental study gallium arsenide gene replacement gene therapy improved infancy innovation motor recovery mouse model neural neurophysiology novel novel therapeutics preservation prevent repaired respiratory respiratory disease/disorder therapy skeletal skills standard of care targeted treatment

项目摘要

PROJECT SUMMARY Candidate & Environment: The short and long-term goals of the candidate are to gain skills, knowledge, and experience necessary to become a successful independent investigator in gene therapy for neuromuscular diseases (NMDs) with respiratory pathology, such as Pompe disease. Duke University is the optimal location for the candidate to achieve these goals with a world-renowned Pompe disease clinical and research center, along with myology and gene therapy experts, who frequently collaborate and who host monthly research seminars. Research: Pompe disease is a fatal glycogen storage disease caused by mutations in the gene encoding acid α-glucosidase (GAA), which is responsible for hydrolyzing lysosomal glycogen. GAA deficiency results in glycogen accumulation in the lysosomes of muscles (cardiac, skeletal, smooth) and motor neurons. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA). ERT effectively treats cardiac muscle glycogen accumulation but cannot completely correct skeletal muscle pathology due to disrupted autophagy. In addition, ERT cannot cross the blood-brain barrier to treat motor neurons, and therefore, respiratory failure persists. Thus, to prevent respiratory distress in Pompe patients, there is a need for therapies that can clear glycogen and repair autophagy in the respiratory muscles and motor neurons. The overall goal is to identify novel adjunctive therapies to improve respiratory muscle and motor neuron pathology in Pompe disease. We propose to administer three autophagy activators which can cross the blood- brain barrier and assess their therapeutic impact on the motor unit of Pompe mice (Gaa-/-). Acute intermittent hypoxia (AIH), rapamycin, and recombinant adeno-associated virus (rAAV) gene therapy are potential therapies to treat Pompe disease, which will be evaluated across three aims. Each therapeutic has a unique and complementary ability to address autophagy, a critical component of Pompe disease cellular therapy, in key respiratory muscles and motor neurons. (1) Hypoxia is an activator of the autophagosome initiation complex. Additionally, AIH induces neuroplasticity in respiratory motor neurons in neurogenerative disorders. (2) Rapamycin is currently administered to Pompe patients as an immune suppressor, however, rapamycin also has a direct negative impact on master metabolic regulator, mTORC1, thus activating autophagy. (3) rAAV-GAA provides the deficient enzyme, thereby reducing glycogen and improving lysosome health which is a key to restoring normal autophagy. In the final aim of this proposal, we will combine rAAV-GAA therapy with AIH and rapamycin to determine the cumulative effect. Key methods of analysis include neurophysiology to assess neural output of respiratory nerves, whole body plethysmography to assess respiration, molecular proteomics analysis for autophagy pathway proteins, and immunohistochemistry to identify cellular architecture of muscle and CNS. These novel interventions are already used in clinical trials and have the potential to quickly translate to clinical care in Pompe patients suffering from respiratory distress.

项目概要候选人和环境：候选人的短期和长期目标是获得技能、知识和成为神经肌肉基因治疗成功的独立研究者所必需的经验具有呼吸道病理学的疾病（NMD），例如庞贝病，杜克大学是治疗的最佳地点。与世界著名的庞贝病临床和研究中心一起实现这些目标的候选人与肌肉学和基因治疗专家合作，他们经常合作并每月举办研究研讨会。研究：庞贝病是一种致命的糖原累积病，由编码酸的基因突变引起 α-葡萄糖苷酶 (GAA) 负责水解溶酶体糖原，导致 GAA 缺乏。肌肉（心肌、骨骼、平滑肌）和运动神经元溶酶体中糖原的积累。 FDA 批准的治疗方法是重组人 GAA (rhGAA) 的酶替代疗法 (ERT)。有效治疗心肌糖原积累，但不能完全纠正骨骼肌病理由于自噬被破坏，ERT 无法穿过血脑屏障来治疗运动神经元，并且因此，呼吸衰竭持续存在。因此，为了预防庞贝氏症患者的呼吸窘迫，需要采取措施。可以清除糖原并修复呼吸肌和运动神经元自噬的疗法。总体目标是确定新的辅助疗法来改善呼吸肌和运动神经我们建议使用三种可以穿过血液的自噬激活剂。脑屏障并评估其对 Pompe 小鼠运动单位（Gaa-/-）的治疗影响。缺氧（AIH）、雷帕霉素和重组腺相关病毒（rAAV）基因疗法是潜在的疗法治疗庞贝氏症，将根据三个目标进行评估，每种疗法都有其独特的特点。解决自噬问题的补充能力是庞贝病细胞治疗的关键组成部分 (1) 缺氧是自噬体起始复合物的激活剂。此外，AIH 还可诱导神经生成性疾病中呼吸运动神经元的神经可塑性 (2)。雷帕霉素目前作为免疫抑制剂用于庞贝氏症患者，然而，雷帕霉素也有对主要代谢调节因子 mTORC1 产生直接负面影响，从而激活自噬 (3) rAAV-GAA。提供缺乏的酶，减少糖原并改善溶酶体健康，这是恢复正常的自噬在本提案的最终目标中，我们将 rAAV-GAA 疗法与 AIH 结合起来。雷帕霉素确定累积效应的关键分析方法包括评估神经的神经生理学。呼吸神经的输出、评估呼吸的全身体积描记法、分子蛋白质组学分析用于自噬途径蛋白，以及免疫组织化学来识别肌肉和中枢神经系统的细胞结构。这些新颖的干预措施已用于临床试验，并有可能快速转化为临床患有呼吸窘迫的庞贝病患者的护理。