Enzyme replacement therapy for Sanfilippo A lysosomal rare disease

 描述(由申请人提供)：这项SBIR提案的目标是通过利用植物性酶生物生产的安全性、供应量和成本优势，同时整合BioStrategy LC正在开发的新的ERT交付策略，为Sanfilippo A患者开发有效的酶替代疗法(ERT)。Sanfilippo A(MPS-IIIA)是一种罕见的遗传性溶酶体储存障碍，在美国影响不到20万人。它是由编码肝素N-硫酸酯酶(SGSH)的基因缺陷引起的，其特征是儿童正常发育，特别是大脑功能的进行性退化，导致幼年死亡。目前的治疗选择仅限于症状管理，有效的ERT药物的开发受到将这些药物输送到大脑和中枢神经系统(CNS)的挑战。如果成功，这项SBIR将为Sanfilippo A患者带来有效的基于ERT的治疗，这是一个迫切需要但选择有限的患者群体。利用BioStrategy在该项目期间进一步开发的新的植物凝集素-ERT融合和递送技术，这项研究可能导致基于ERT的治疗方法的根本范式转变，该方法基于创新的替代细胞靶向机制和跨血脑屏障(BBB)药物递送。最近，FDA批准了Protalix/辉瑞公司用于治疗高谢病的植物制成的葡萄糖脑苷酶ERT Elelyso，从而确认了该项目中采用植物制成的生物生产的前景。适销对路的产品潜力很大。随着罕见疾病社区对减少药物开发和生产的时间表和成本表现出越来越大的兴趣，我们利用基于植物的生物生产的新的ERT药物技术将具有极大的吸引力和竞争力。该SBIR项目的所有第一阶段目标已经实现，证明了a)使用植物为基础的生物制造我们的复杂人类基因产品的可行性，以及b)我们的凝集素载体能够中介将活性磺胺酶输送到人类细胞和溶酶体内，从而纠正MPS-IIIA疾病的表型。这项第二阶段的SBIR建议旨在实现以下后续目标：1)生产规模和纯度高的生物活性SGSH：凝集素融合药物产品，以支持体内小鼠模型动物试验；2)评估正常小鼠和MPS-IIIA小鼠体内的酶分布；以及3)评估我们的候选先导药物在MPS-IIIA小鼠模型中的疾病纠正效果。第二阶段的成功将证明我们的凝集素候选药物在纠正这种疾病的小鼠模型中的体内疾病表型方面的有效性，支持后续的临床前疗效和毒理学研究，这是成功向FDA申请IND以启动人类临床试验所需的。

 DESCRIPTION (provided by applicant): The goal of this SBIR proposal is to develop an effective enzyme replacement therapy (ERT) for Sanfilippo A patients by exploiting safety, supply, and cost advantages of plant-based enzyme bioproduction while integrating novel ERT delivery strategies being development at BioStrategies LC. Sanfilippo A (MPS-IIIA) is a rare genetic lysosomal storage disorder affecting less than 200,000 people in the U.S. It is caused by a defect in the gene encoding the enzyme heparan N-sulfatase (SGSH) and is characterized by progressive degeneration in normal childhood development especially in brain function leading to death at an early age. Current treatment options are limited to symptom management and development of an effective ERT drug has been hindered by challenges of delivering these drugs to the brain and central nervous system (CNS). If successful, this SBIR will lead to an effective ERT-based treatment for Sanfilippo A patients, a patient population with desperate need and limited options. Utilizing BioStrategies' new plant lectin-ERT fusion and delivery technology to be further developed during this project, this research could lead to a fundamental paradigm shift for ERT-based treatment approaches based on innovative alternate cell targeting mechanisms, and trans-blood-brain-barrier (BBB) drug delivery. The promise of plant-made bio-production to be employed in this project has recently been recognized with the FDA approval of Elelyso, Protalix/Pfizer's plant-made glucocerebrosidase ERT for Gaucher Disease. The potential for a marketable product is high. With the rare disease community showing escalating interest in reducing drug development and production timelines and costs, our new ERT drug technology utilizing plant- based bio-production will be highly attractive and competitive. All Phase I objectives of this SBIR project have been met demonstrating a) the feasibility of using plant- based bio-manufacturing for our complex human gene product and b) the ability of our lectin carriers to mediate delivery of active sulfamidase into human cells and lysosomes leading to MPS-IIIA disease phenotype correction. This Phase II SBIR proposal addresses the following follow-on objectives: 1) To produce bioactive SGSH:lectin fusion drug products at scale and purity to support in vivo mouse model animal trials, 2) To evaluate in vivo enzyme distribution in normal and MPS-IIIA mice, and 3) To assess efficacy in disease correction of our lead drug candidate in the MPS-IIIA mouse model. Success in Phase II will demonstrate the efficacy of our lectin drug candidate to correct in vivo disease phenotype in the mouse model for this disease supporting subsequent preclinical efficacy and toxicology studies required for a successful IND application to FDA to initiate human clinical trials.