Stable therapy in Pompe disease through genome editing

通过基因组编辑稳定治疗庞贝病

基本信息

批准号：
10459479
负责人：
Dwight D Koeberl
金额：
$ 64.24万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459479
关键词：
Acids Address Adult Antibodies Antibody Response Biochemical Blood Blood Circulation Clinical Trials Dependovirus Development Disease Early treatment Enrollment Future Genes Genetic Recombination Glucan 1,4-alpha-Glucosidase Glycogen Glycogen storage disease type II Goals Heart Human Immune response Immunosuppression In Vitro In complete remission Infant Life Liver Mediating Metabolic Diseases Methods Modeling Mus Muscle Muscle Weakness Muscle function Muscular Atrophy Myocardium Nervous system structure Patients Pharmaceutical Preparations Phase I Clinical Trials Population Production Quality of life Recombinants Regimen Regulatory T-Lymphocyte Skeletal Muscle Symptoms Testing Therapeutic Transgenes Translating Variant adeno-associated viral vector design enzyme replacement therapy experience gene replacement therapy gene therapy genome editing glucosidase improved in vivo infancy intravenous administration mouse model novel therapeutics pre-clinical research prevent receptor standard of care therapeutic genome editing therapeutic transgene therapy development uptake vector vector genome

项目摘要

The need for treatment early in life has emerged as an unmet need in Pompe disease (acid maltase deficiency; glycogen storage disease type II), a lysosomal storage disorder caused by acid -glucosidase (GAA) deficiency that leads to the accumulation of lysosomal glycogen and debilitating weakness. Patients with Pompe disease receive life-prolonging therapy with enzyme replacement therapy (ERT) consisting of recombinant human GAA; however, ERT fails to completely reverse symptoms including glycogen storage and functional deficits. The lack of a complete response to ERT has stimulated the development of new therapies, including gene therapy. Gene therapy development has largely overlooked the need for early treatment during preclinical research. We propose to address the question of how gene therapy for Pompe disease can reverse nervous system involvement through the following Specific Aims: 1) Translate genome editing that establishes a stable depot for GAA to the liver early in life; 2) Evaluate personalized genome editing for the treatment of Pompe disease early in life. Developing gene therapy in Pompe disease may provide benefits in comparison with ERT, including the correction of skeletal muscle and enhanced quality of life. These Specific Aims will address the need for treatment early in life in Pompe disease by developing genome editing, which will guide the design of future clinical trials to develop highly effective genetic therapy.

生命早期对治疗的需求已成为蓬松疾病的未满足需要（酸性麦芽糖酶缺乏症；糖原储存疾病II型），一种由酸-葡萄糖苷酶（GAA）引起的溶酶体储存障碍导致溶酶体糖原积累和使虚弱的弱点的缺乏。患者庞贝疾病通过酶替代疗法（ERT）接受生命疗法，包括重组人GAA；但是，ERT无法完全逆转症状，包括糖原储存和功能不足。缺乏对ERT的完全反应刺激了新疗法的发展，包括基因疗法。基因疗法的开发在很大程度上忽略了对早期治疗的需求临床前研究。我们建议解决庞贝疾病基因疗法如何逆转的问题神经系统通过以下特定目的参与：1）翻译建立的基因组编辑 GAA的稳定仓库，生命早期肝脏； 2）评估个性化基因组编辑以治疗生命早期庞贝疾病。在庞贝疾病中开发基因疗法可能会带来相比的好处使用ERT，包括矫正骨骼肌和增强的生活质量。这些具体目标将通过开发基因组编辑来满足庞贝疾病早期治疗的需求，这将指导未来临床试验的设计以开发高效的基因疗法。