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

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.

目前无法有效地提供正确剂量的溶酶体参与肌肉疾病症状的关键细胞的酶仍然是一个重要的因素罕见溶酶体疾病（LSD）的障碍，例如庞贝病和其他具有明显肌肉骨骼病理的类似疾病。正在开发植物凝集素 RTB 作为能够扩展酶的载体输送到“难以治疗”的器官和组织，包括大脑、心脏和最近已显示凝集素介导的 ERT 传递。其他 LSD 中的承诺，包括 MPS I 和 GM1，此 SBIR 重点关注。为患者开发“增强递送”酶替代疗法（ERT）庞贝病是一种由遗传引起的常染色体隐性LSD。酸性α-葡萄糖苷酶（GAA）缺乏导致进行性多器官功能障碍病理学特别关注平滑肌、心脏和严重的庞贝氏症可导致骨骼肌死亡。广泛的心肌病和呼吸肌衰竭。我们在这个研究项目中的长期目标是提供一种能够治疗的 ERT 全面的进行性肌肉和其他疾病表现 I 期 SBIR 可行性研究的目标是产生庞贝氏症患者。生物活性 GAA:RTB 融合并证明 ERT 产品可输送至人体肌细胞、庞贝细胞溶酶体表型的校正和生物分布庞贝小鼠模型中的骨骼肌、心脏和其他组织。第一阶段的可行性目标将支持进入严格的第二阶段 SBIR 后续行动进行临床前评估，旨在将这种有前途的 ERT 产品转入 IND。这里建立的可行性也将支持扩展 RTB 承运系统针对其他危及生命的疾病的额外 ERT 药物和疗法肌肉病理学。