Novel Adjunctive Therapies for Pompe Disease

庞贝病的新型辅助疗法

基本信息

批准号：
10351044
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/10351044
关键词：
Acute Address Affect Architecture Automobile Driving Autophagocytosis Autophagosome Blood Blood - brain barrier anatomy Brain Breathing Cardiac Cell Therapy Childhood Clinical Research Clinical Treatment Clinical Trials 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 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 Phase I Clinical Trials Phase II Clinical Trials 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 career clinical care disease-causing mutation enzyme replacement therapy experience experimental study gallium arsenide gene replacement gene therapy improved infancy innovation motor recovery mouse model neurophysiology novel novel therapeutics preservation prevent relating to nervous system 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.

项目摘要候选人与环境：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疗法成功独立研究者所需的经验患有呼吸道病理学的疾病（NMD），例如蓬松疾病。杜克大学是最佳位置通过世界知名的庞贝疾病临床和研究中心实现这些目标的候选人与经常合作并举办每月研究中心的肌科和基因疗法专家。研究：庞贝疾病是由编码酸的基因突变引起的致命糖原储存疾病 α-葡萄糖苷酶（GAA），负责水解溶酶体糖原。 GAA缺乏导致糖原积累在肌肉（心脏，骨骼，光滑）和运动神经元的溶酶体中。唯一的 FDA批准的治疗是重组人GAA（RHGAA）的酶替代疗法（ERT）。 ERT 有效治疗心肌糖原的积累，但不能完全纠正骨骼肌肉病理学由于自噬而破坏。此外，ERT不能跨越血脑屏障来治疗运动神经元，并且因此，呼吸衰竭仍然存在。为了防止庞贝患者的呼吸窘迫，需要可以清除糖原并修复呼吸肌和运动神经元中自噬的疗法。总体目标是确定新型的辅助疗法以改善呼吸肌肉和运动神经元庞贝疾病的病理学。我们建议管理三个可以跨过血液的自噬激活剂脑屏障并评估其对庞贝小鼠运动单元（GAA - / - ）的治疗影响。急性间歇性缺氧（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疾病，将在三个目标中进行评估。每种疗法都有独特的互补的能力解决自噬，这是庞贝疾病细胞疗法的关键成分，呼吸道肌肉和运动神经元。（1）缺氧是自噬体倡议复合物的激活剂。另外，AIH在神经发生疾病中诱导呼吸运动神经元中的神经可塑性。（2）雷帕霉素目前是作为免疫抑制剂的庞贝患者给药的，但是，雷帕霉素也具有直接对主代谢调节剂MTORC1的负面影响，从而激活自噬。（3）Raav-Gaa 提供不足的酶，从而减少糖原并改善溶酶体健康，这是一个关键恢复正常的自噬。在该提案的最后目的中，我们将将Raav-GAA疗法与AIH和AIH结合起来雷帕霉素确定累积作用。分析的关键方法包括评估神经生理学的神经生理学呼吸道神经的输出，全身分布术，以评估呼吸，分子蛋白质组学分析用于自噬途径蛋白和免疫组织化学，以鉴定肌肉和中枢神经系统的细胞结构。这些新颖的干预措施已经用于临床试验，并有可能快速转化为临床患有呼吸窘迫的庞贝患者的护理。