Enzyme replacement therapy for Sanfilippo A lysosomal rare disease

 描述（由申请人提供）：本SBIR提案的目标是通过利用植物酶生物生产的安全性、供应和成本优势，同时整合BioStrategies LC正在开发的新型ERT输送策略，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贮积症，在美国影响不到20万人，它是由编码乙酰肝素N-硫酸酯酶（SGSH）的基因缺陷引起的，其特征是正常儿童发育，特别是脑功能的进行性退化，导致早期死亡。目前的治疗选择仅限于症状管理，并且有效的ERT药物的开发受到将这些药物递送至大脑和中枢神经系统（CNS）的挑战的阻碍。如果成功，SBIR将为Sanfilippo A患者提供有效的基于ERT的治疗，这是一个迫切需要和选择有限的患者群体。 利用BioStrategies在本项目期间进一步开发的新型植物凝集素-ERT融合和递送技术，这项研究可能会导致基于创新替代细胞靶向机制和跨血脑屏障的ERT治疗方法的根本性范式转变（BBB）药物递送。该项目中采用植物生物生产的前景最近得到了FDA批准Elelyso，Protalix/Pfizer的植物葡萄糖脑苷脂酶ERT用于戈谢病。市场化产品的潜力很大。随着罕见病界对缩短药物开发和生产时间表和成本的兴趣不断增强，我们利用植物生物生产的新型ERT药物技术将具有高度吸引力和竞争力。 该SBIR项目的所有I期目标均已实现，证明了a）使用基于植物的生物制造用于我们的复杂人基因产物的可行性和B）我们的凝集素载体介导活性磺酰胺酶递送至人细胞和溶酶体中导致MPS-IIIA疾病表型校正的能力。该II期SBIR提案解决了以下后续目标：1）以支持体内小鼠模型动物试验的规模和纯度生产生物活性SGSH：凝集素融合药物产品，2）评价正常和MPS-IIIA小鼠中的体内酶分布，以及3）评估我们的先导候选药物在MPS-IIIA小鼠模型中的疾病矫正功效。II期的成功将证明我们的凝集素候选药物在该疾病的小鼠模型中纠正体内疾病表型的功效，支持向FDA成功申请IND以启动人体临床试验所需的后续临床前功效和毒理学研究。

 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.