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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.

项目总结