Improving MPS I ERT Efficacy through Lectin-Mediated Delivery

本项目的长期目标是为MPS I患者开发一种改进的ERT，其创新点是 增强ERT输送和难以治疗的器官（如大脑）的疾病矫正， 植物性生物生产的安全性和成本优势。MPS I综合征是由遗传 溶酶体酶α-L-艾杜糖醛酸酶（IDUA）缺乏。虽然目前用于MPS I的ERT药物选择 有效地治疗许多内脏器官，这种疾病在中央的显着衰弱表现 中枢神经系统（CNS）仍有待解决。BioStrategies先前的细胞研究表明， 这种凝集素对哺乳动物细胞表面上常见的糖蛋白和糖脂具有高亲和力， 可介导IDUA的有效细胞摄取、转胞吞作用和向溶酶体的递送。体外分析 用我们的IDUA-凝集素融合物（称为IDUAL）处理的MPS I患者成纤维细胞显示出快速和 有效纠正细胞疾病表型。我们对这个项目的第一阶段可行性动物研究 已经表明IDUAL可以被递送到MPS I小鼠模型动物的脑中， 纠正这种疾病的细胞和行为表型， I期研究的目的。该后续II期提案的具体目标是：1）体内评估 MPS I小鼠中的药物剂量水平、频率和CNS药物递送和功效读数，2）开发 IDUAL产品规模扩大、稳定性和确认方案，以支持高级临床前研究，以及 3)建立严格的临床前动物数据，评估疗效、治疗开始时的年龄、免疫原性， 性别效应和长期IDUAL给药后的行为矫正。 该项目第一阶段目标的实现显示了在体内细胞和行为动物功效， IDUAL为我们的凝集素载体ERT融合药物递送技术提供了关键的概念验证。 这个二期更新项目的总体目标将是完成下一阶段的药物生产 大规模的，高度严谨的动物研究，将为后续的临床前研究奠定坚实的基础。 支持IND申请成功启动临床试验所需的研究。 我们对该项目的成功概念验证研究的进一步推进将为潜在的 将这种基于凝集素的药物递送技术平台应用于多种其他先前的药物递送技术， 很难治疗疾病。

The long-term goal of this project is to develop an improved ERT for MPS I patients with innovations that enhance ERT delivery and disease correction in hard to treat organs such as the brain while integrating safety and cost advantages of plant-based bioproduction. MPS I Syndrome is caused by genetic deficiencies in the lysosomal enzyme α-L-iduronidase (IDUA). While current ERT drug options for MPS I effectively treat many visceral organs, significant debilitating manifestations of this disease in the central nervous system (CNS) remain to be addressed. Previous cellular studies by BioStrategies showed that this lectin, which has high affinity for glycoproteins and glycolipids common on mammalian cell surfaces, can mediate efficient cellular uptake, transcytosis, and delivery of IDUA to lysosomes. In vitro analyses of MPS I patient fibroblasts treated with our IDUA-Lectin fusion (termed IDUAL) demonstrated rapid and efficient correction of cellular disease phenotypes. Our Phase I feasibility animal studies on this project have shown that IDUAL could be delivered to the brains of MPS I mouse model animals yielding correction of both cellular and behavioral phenotypes of this disease and achieving the milestone objectives of the Phase I study. Specific aims for this follow-up Phase II proposal are 1) Assess in vivo drug dosage levels, frequency, and CNS drug delivery and efficacy readouts in MPS I mice, 2) Develop IDUAL product scale-up, stability, and qualification protocols to support advanced preclinical studies, and 3) Establish rigorous preclinical animal data assessing efficacy, age at treatment onset, immunogenicity, gender effects, and behavioral correction following long-term IDUAL administration. Achievement of phase I goals of this project showing in vivo cellular and behavioral animal efficacy of IDUAL has provided a critical proof-of-concept for our lectin carrier ERT fusion drug delivery technology. The overall goal of this Phase II renewal project will be to complete the next stage of drug production scale-up, and highly rigorous animal studies that will lay a solid foundation for the follow-up preclinical research that will be required to support a successful IND application for initiating clinical trails. Furtherance of our successful proof-of concept studies on this project will build a solid basis for potential applications of this lectin based drug delivery technology platform to a wide variety of other previously hard to treat diseases.