Enzyme Replacement Therapy for Sanfilippo A Lysosomal Rare Disease

描述（由申请人提供）：本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给药策略，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性疾病，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，其特征是在正常的儿童发育过程中进行性退化，尤其是在大脑功能方面，导致早期死亡。目前的治疗选择仅限于症状管理，有效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）的挑战的阻碍。最近，FDA批准了Elelyso (taliglucerase)，这是Protalix/辉瑞公司用于治疗戈谢病的植物性葡萄糖脑苷酶ERT，植物性生物生产的前景得到了认可。如果成功，该SBIR将为Sanfilippo A患者带来有效的基于ert的治疗，这是一个迫切需要和有限选择的患者群体。利用BioStrategies在该项目中进一步开发的新型植物凝集素- ert融合和传递技术，该研究将导致基于创新的替代细胞靶向机制，粘膜传递和跨血脑屏障（BBB）活性的基于ert的治疗方法的基本范式转变。产品的市场潜力非常大。随着最近FDA批准植物制造Elelyso，以及行业对罕见疾病靶点的兴趣增加，降低药物开发和生产成本/时间表，这些基于植物的生物生产新技术具有很强的竞争力。独立于凝集素传递方面，植物源性SGSH将比哺乳动物细胞源性SGSH ERT具有成本和安全性优势。如果凝集素介导ERT传递的前景得到满足，凝集素：SGSH融合将成为MSP-IIIA的一种治疗选择，这种药物传递技术可以广泛地开发用于其他具有强烈中枢神经系统累及或经黏膜传递适应症的疾病。该一期项目将解决以下具体问题：a)植物是否能够生产具有生物活性的人肝素硫酸酯酶（SGSH）？b)能否产生既保留SGSH酶活性又保留碳水化合物结合选择性的SGSH -植物凝集素融合物？c)这些植物蛋白是否被输送到体外的Sanfilippo A细胞模型中并进行校正？I期的成功将证明基于植物的生物生产生物活性SHSG和凝集素与SGSH融合ERT的可行性，并将支持随后的II期研究，以进一步表征产品，扩大生产以支持动物试验，在MSP-IIIA小鼠模型中进行体内疾病纠正和ERT功效研究，以及评估血脑屏障转细胞作用和中枢神经系统疾病底物清除。

DESCRIPTION (provided by applicant): The goal of this 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 heparin 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). The promise of plant-made bioproduction has recently been recognized with the FDA approval of Elelyso (taliglucerase), Protalix/Pfizer's plant-made glucocerebrosidase ERT for Gaucher Disease. 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 will lead to a fundamental paradigm shift for ERT-based treatment approaches based on innovative alternate cell targeting mechanisms, mucosal delivery, and trans-blood-brain-barrier (BBB) activity. The potential for a marketable product is very high. With the recent FDA approval of plant-made Elelyso and industry showing elevated interest in rare disease targets and lowering drug development and production cost/timelines, these new technologies for plant-based bioproduction are highly competitive. Independent of the lectin delivery aspects, plant-derived SGSH will bring cost and safety advantages over mammalian cell-derived SGSH ERT. If the promise of lectin- mediated ERT delivery is met, lectin:SGSH fusions would be a treatment of choice for MSP-IIIA and this drug delivery technology could be broadly developed to target other diseases with strong CNS involvement or indications for transmucosal delivery. This Phase I project will address the following specific questions: a) Are plants capable of producing bioactive human heparin sulfatase (SGSH)?, b) Can SGSH - plant lectin fusions be produced that retain both SGSH enzyme activity and carbohydrate binding selectivity?, and c) Are these plant-made proteins delivered to and corrective in in vitro Sanfilippo A cell models. Success in Phase I will demonstrate the feasibility of plant-based bioproduction of bioactive SHSG and the lectin-fusion ERT with SGSH and will support subsequent Phase II studies to further product characterization, scaled-up production to support animal trials, in vivo disease correction and ERT efficacy studies in MSP-IIIA mouse models, and assessment of BBB transcytosis and CNS disease substrate clearance.