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

目前无法有效地提供校正剂量的溶酶体 参与肌肉疾病症状的关键细胞的酶仍然是一个重要的 罕见溶酶体疾病(LSD)的障碍，如庞贝病和其他 有明显肌肉骨骼病变的类似疾病。生物策略LC 正在开发植物凝集素rtb作为能够扩张酶的载体 输送到“难以治疗”的器官和组织，包括大脑、心脏和 骨骼肌组织。凝集素介导的ERT传递最近显示 在其他LSD中的承诺，包括MPS I和GM1。这份SBIR的重点是 为患者开发“交付增强型”酶替代疗法(ERT) 患有庞培病。Pompe是一种由遗传引起的常染色体隐性遗传性LSD 酸性α-葡萄糖苷酶(GAA)缺陷导致进行性多器官损害 病理学特别集中在光滑、心脏和心脏的严重症状 骨骼肌。严重的庞贝病可能会导致死亡，原因是 广泛性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带来一种能够治疗的ERT 进行性肌肉和其他疾病的全方位表现 庞贝病人。这项第一阶段SBIR可行性研究的目标是 生物活性GAA：RTB融合并展示ERT产品进入人体 庞贝细胞中溶酶体表型的校正和生物分布 Pompe小鼠模型中的骨骼肌、心脏和其他组织。成功 在第一阶段的可行性目标中，将支持进入严格的第二阶段SBIR： UP临床前评估旨在将这一有前景的ERT产品转移到IND。 在此确立的可行性也将支持扩大RTB载波系统 其他有生命危险的疾病的ERT药物和治疗方法 肌肉病理学。

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.