Treatment of muscular symptoms in Pompe rare disease via lectin assisted ERT delivery

通过凝集素辅助 ERT 治疗庞贝氏症罕见病的肌肉症状

基本信息

批准号：
9975954
负责人：
CAROLE L. CRAMER
金额：
$ 25万
依托单位：
BIOSTRATEGIES, LC
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2022-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975954
关键词：
Address Affect Agrobacterium Alpha-glucosidase Antibodies Antibody Response Binding Biodistribution Biological Blood - brain barrier anatomy Brain Breathing Carbohydrates Cardiac Cardiomyopathies Cause of Death Cell Line Cells Cessation of life Chimeric Proteins Data Development Disease Disease Progression Dose Drug Delivery Systems Enzymes Exhibits Failure Family Feasibility Studies Fibroblasts Functional disorder Galactosamine Galactose Genetic Genetic Diseases Glucan 1,4-alpha-Glucosidase Glycogen Glycogen storage disease type II Glycolipids Goals Health system Heart Human Human Genetics Immune Sera Immune response In Vitro Infant Kinetics Knockout Mice Lead Lectin Life Lysosomes Mammalian Cell Mediating Medical Membrane Glycoproteins Metabolic Diseases Motor Mucopolysaccharidosis I Mucopolysaccharidosis I H Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscle Weakness Myocardium Myopathy Neuraxis Nicotiana Organ Pathogenicity Pathology Patients Pharmaceutical Preparations Phase Phenotype Plant Lectins Plants Production Progressive Disease Public Health Rare Diseases Research Research Project Grants Respiratory Diaphragm Respiratory Failure Respiratory Muscles Skeletal Muscle Small Business Innovation Research Grant Smooth Muscle Symptoms System Technology Testing Therapeutic Tissues base blood-brain barrier crossing cell type cost disease phenotype drug efficacy enzyme activity enzyme replacement therapy follow-up glucosidase in vivo innovation mouse model muscular system neutralizing antibody phase 2 study pre-clinical public health relevance rare genetic disorder receptor respiratory skeletal skeletal disorder success transcytosis uptake

Address Affect Agrobacterium Alpha-glucosidase Antibodies Antibody Response Binding Biodistribution Biological Blood - brain barrier anatomy Brain Breathing Carbohydrates Cardiac Cardiomyopathies Cause of Death Cell Line Cells Cessation of life Chimeric Proteins Data Development Disease Disease Progression Dose Drug Delivery Systems Enzymes Exhibits Failure Family Feasibility Studies Fibroblasts Functional disorder Galactosamine Galactose Genetic Genetic Diseases Glucan 1,4-alpha-Glucosidase Glycogen Glycogen storage disease type II Glycolipids Goals Health system Heart Human Human Genetics Immune Sera Immune response In Vitro Infant Kinetics Knockout Mice Lead Lectin Life Lysosomes Mammalian Cell Mediating Medical Membrane Glycoproteins Metabolic Diseases Motor Mucopolysaccharidosis I Mucopolysaccharidosis I H Mus Muscle Muscle Cells Muscle Development Muscle Fibers Muscle Weakness Myocardium Myopathy Neuraxis Nicotiana Organ Pathogenicity Pathology Patients Pharmaceutical Preparations Phase Phenotype Plant Lectins Plants Production Progressive Disease Public Health Rare Diseases Research Research Project Grants Respiratory Diaphragm Respiratory Failure Respiratory Muscles Skeletal Muscle Small Business Innovation Research Grant Smooth Muscle Symptoms System Technology Testing Therapeutic Tissues base blood-brain barrier crossing cell type cost disease phenotype drug efficacy enzyme activity enzyme replacement therapy follow-up glucosidase in vivo innovation mouse model muscular system neutralizing antibody phase 2 study pre-clinical public health relevance rare genetic disorder receptor respiratory skeletal skeletal disorder success transcytosis uptake

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项目摘要

The current inability to effectively deliver corrective doses of lysosomal enzymes to key cells involved in muscular disease symptoms remains a significant hurdle for rare lysosomal disorders (LSD) such as Pompe disease and other similar diseases with significant muscular-skeletal pathologies. BioStrategies LC is developing the plant lectin RTB as a carrier capable of expanding enzyme delivery to “hard-to-treat” organs and tissues including the brain, heart, and skeletal muscle tissues. Lectin-mediated ERT delivery has recently shown promise in other LSDs including MPS I and GM1. This SBIR is focused on developing a “delivery-enhanced” enzyme replacement therapy (ERT) for patients with Pompe disease. Pompe is an autosomal recessive LSD caused by genetic deficiencies in acid alpha-glucosidase (GAA) leading to progressive multi-organ pathologies particularly focused on severe symptoms in smooth, cardiac and skeletal muscles. Pompe disease in its severe forms can lead to death due to extensive cardiomyopathy and respiratory muscle failure. Our long-term goal in this research project is to bring an ERT capable of treating the full spectrum of progressive muscular and other disease manifestations to Pompe patients. Objectives of this Phase I SBIR feasibility study are to produce bioactive GAA:RTB fusions and demonstrate ERT product delivery into human myocytes, correction of lysosomal phenotype in Pompe cells, and biodistribution to skeletal muscle, heart, and other tissues in the Pompe mouse model. Success in Phase I feasibility goals will support moving on to rigorous Phase II SBIR follow- up preclinical assessments aimed at moving this promising ERT product to an IND. The feasibility established here will also support expanding the RTB carrier system to additional ERT drugs and therapeutics for other diseases having life-threatening muscle pathologies.

当前无法有效提供正确剂量的溶酶体涉及参与肌肉疾病症状的关键细胞的酶仍然是重要的罕见溶酶体疾病（LSD）的障碍，例如庞贝疾病和其他具有明显肌肉骨骼病理的类似疾病。 BioStrategies LC 正在开发植物讲座RTB作为能够扩展酶的载体传递到包括大脑，心脏和骨骼肌组织。凝集素介导的ERT输送最近显示了在包括MPS I和GM1在内的其他LSD中承诺。这个SBIR专注于为患者开发“递送增强”酶替代疗法（ERT）患有庞贝疾病。庞贝是由遗传引起的常染色体隐性LSD 酸性α-葡萄糖苷酶（GAA）的缺陷导致进行性多器官病理特别关注光滑，心脏和心脏的严重症状骨骼肌。以其严重形式的庞贝疾病可能导致死亡广泛的心肌病和呼吸道肌肉衰竭。我们在该研究项目中的长期目标是带来一个能够治疗的ERT 全面进行性肌肉和其他疾病表现庞贝患者。该阶段I SBIR可行性研究的目标是生成生物活性GAA：RTB融合并将ERT产品传递到人类心肌细胞，易蛋白质细胞中溶酶体表型的校正和生物分布在庞贝小鼠模型中，骨骼肌，心脏和其他组织。成功在第一阶段的可行性中，目标将支持继续进行严格的II期SBIR跟随 - 旨在将这种承诺的ERT产品转移到IND的临床前评估。这里建立的可行性还将支持扩展RTB载体系统为其他威胁生命的疾病的其他ERT药物和治疗肌肉病理。