Improving MPS I ERT Efficacy through Lectin-Mediated Delivery

通过凝集素介导的递送提高 MPS I ERT 功效

• 批准号: 8647715
• 负责人: CAROLE L. CRAMER
• 金额: $ 45.83万
• 依托单位: BIOSTRATEGIES, LC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647715
• 关键词: Address; Affect; Affinity; Antibodies; Behavior; Behavioral; Binding; Biochemical; Biodistribution; Blood - brain barrier anatomy; Brain; Cell surface; Cells; Characteristics; Chemicals; Chimeric Proteins; Clinic; Clinical; Clinical Trials; Clinical Trials Design; Cognitive; Cyclic GMP; Disease; Disease Progression; Dose; Drug Delivery Systems; Drug Kinetics; Effectiveness; Enzymes; Exhibits; Family; Feasibility Studies; Fibroblasts; Galactosamine; Galactose; Genetic; Glycolipids; Glycoproteins; Glycosaminoglycans; Goals; Healthcare Systems; Hereditary Disease; Histopathology; Human; Human Genetics; IGF Type 2 Receptor; In Vitro; Kentucky; Knockout Mice; L-Iduronidase; Lectin; Liver; Lysosomes; Mammalian Cell; Mediating; Minnesota; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mucopolysaccharidosis I S; Mus; Neuraxis; Organ; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology and Toxicology; Phase; Plant Lectins; Plants; Process; Production; Proteins; Public Health; Qualifying; Recombinant Proteins; Research; Ricin; Route; Safety; Serum; Small Business Innovation Research Grant; Specificity; Spleen; Symptoms; Technology; Testing; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Universities; Water; animal efficacy; base; bioprocess; brain cell; cell type; cost; disease phenotype; drug candidate; efficacy trial; enzyme activity; improved; in vitro activity; in vivo; innovation; mannose receptor; medical schools; meetings; mouse model; novel therapeutics; patient population; phase 2 study; pre-clinical research; preclinical study; public health relevance; receptor; research and development; research study; scale up; transcytosis; uptake

The long-term goal of this project is to develop an improved enzyme replacement therapeutic (ERT) for MPS I that integrates safety and cost advantages of plant-based bioproduction with innovations that enhance ERT delivery and disease correction. MPS I (encompassing Hurler, Hurler/Scheie, Scheie syndromes), the most common MPS disease, is caused by genetic deficiencies in the lysosomal enzyme ¿-L-iduronidase (IDUA). Current IDUA-based ERTs for MPS I patients effectively treat most somatic symptoms, but do not correct significant debilitating manifestations of this disease, especially those affecting the central nervous system (CNS). To expand the delivery of corrective IDUA enzyme to critical cells and tissues exhibiting MPS I pathology, we have produced fusion proteins that combine IDUA with a galactose/galactosamine-selective plant lectin. This lectin has high affinity for glycoproteins and glycolipids common on mammalian cell surfaces and mediates efficient cellular uptake, transcytosis, and lysosomal delivery of IDUA. In vitro analyses of MPS I patient fibroblasts treated with our IDUA-Lectin fusions (termed IDUAL) demonstrate rapid and efficient correction of cellular disease phenotypes. They also indicate that IDUAL utilizes different cell binding and uptake mechanisms compared to current ERT drugs for lysosomal diseases. We hypothesize that IDUAL will provide ERT access to a broader array of cell types, including cells of the central nervous system, that are not treated by current MPS I drugs. The goal of this SBIR Phase I feasibility study is to assess the in vivo efficacy of the IDUAL fusion as an ERT in the MPS I mouse model. Specific aims for Phase I are 1) to produce IDUAL fusion protein at a scale to support in vivo trials using a transient plant-based expression platform suitable for commercial production, and 2) to demonstrate biodistribution and initial in vivo efficacy of IDUAL in the MPS I mouse model. The in vivo studies will include analyses of cognitive behavior and brain histopathology to assess ERT delivery to the brain and potential for ameliorating CNS pathologies. While our IDUAL fusion protein has shown significant in vitro efficacy in MPS I fibroblasts this SBIR represents the first test of in vivo animal efficacy and will provide a critical proof-of-concept for the lectin carrier and the IDUAL fusion drug candidate. Based on successfully meeting the Phase I milestones, follow-on Phase II research will address key preclinical studies required for filing an IND for this product. In anticipation of this long term goal, BioStrategies LC has initiated clinical and manufacturing partnerships for the Phase II SBIR to support cGMP-like bioproduction scale-up with Kentucky BioProcessing LLC and extended in vivo preclinical research with the University of Minnesota Medical School necessary to support IND filing with FDA and follow- on clinical trials directed toward delivering this technology to affected MPS I patients.

该项目的长期目标是开发一种改进的 MPS I 酶替代疗法 (ERT) 将植物性生物生产的安全性和成本优势与增强 ERT 的创新相结合 分娩和疾病矫正。 MPS I（包括 Hurler、Hurler/Scheie、Scheie 综合征） 常见的 MPS 疾病是由溶酶体酶 ¿-L-艾杜糖醛酸酶 (IDUA) 的遗传缺陷引起的。 目前针对 MPS I 患者的基于 IDUA 的 ERT 可有效治疗大多数躯体症状，但不能纠正 这种疾病的显着衰弱表现，尤其是影响中枢神经系统的表现 （中枢神经系统）。扩大纠正性 IDUA 酶向表现出 MPS I 的关键细胞和组织的递送 病理学方面，我们生产了将 IDUA 与半乳糖/半乳糖胺选择性结合的融合蛋白 植物凝集素。这种凝集素对哺乳动物细胞表面常见的糖蛋白和糖脂具有高亲和力 并介导 IDUA 的有效细胞摄取、转胞吞作用和溶酶体递送。 MPS I 的体外分析 使用我们的 IDUA-凝集素融合物（称为 IDUAL）治疗的患者成纤维细胞表现出快速有效 纠正细胞疾病表型。他们还表明 IDUAL 利用不同的细胞结合和 与目前治疗溶酶体疾病的 ERT 药物相比的吸收机制。我们假设 IDUAL 将 提供 ERT 访问更广泛的细胞类型，包括中枢神经系统细胞 采用目前的 MPS I 药物治疗。 SBIR I 期可行性研究的目标是评估体内功效 IDUAL 融合作为 MPS I 小鼠模型中的 ERT。第一阶段的具体目标是 1) 生产 IDUAL 使用适合于的瞬时植物表达平台以支持体内试验的规模融合蛋白 商业化生产，以及 2) 证明 IDUAL 在 MPS I 中的生物分布和初始体内功效 鼠标模型。体内研究将包括认知行为和脑组织病理学分析 评估 ERT 向大脑的传递以及改善中枢神经系统病理的潜力。 虽然我们的 IDUAL 融合蛋白在 MPS I 成纤维细胞中显示出显着的体外功效，但该 SBIR 代表了动物体内功效的首次测试，并将为凝集素载体提供关键的概念验证 以及 IDUAL 融合候选药物。在成功实现第一阶段里程碑的基础上，后续阶段 II 研究将解决提交该产品 IND 所需的关键临床前研究。预见到这一点 长期目标，BioStrategies LC 已启动 II 期 SBIR 的临床和制造合作伙伴关系，以 与 Kentucky BioProcessing LLC 一起支持类 cGMP 生物生产规模扩大并扩展体内临床前 与明尼苏达大学医学院的研究对于支持向 FDA 提交 IND 申请和后续工作是必要的 旨在向受影响的 MPS I 患者提供这项技术的临床试验。