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: 9346992
• 负责人: Walter Acosta
• 金额: $ 123.7万
• 依托单位: BIOSTRATEGIES, LC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9346992
• 关键词: Achievement; Address; Affect; Affinity; Age; Animal Model; Animals; Behavior; Behavioral; Binding; Biochemical; Biomanufacturing; Blood - brain barrier anatomy; Bone Marrow Transplantation; Brain; Brain region; Cell Culture Techniques; Cell surface; Cells; Central Nervous System Agents; Characteristics; Chimeric Proteins; Clinical; Complication; Cyclic GMP; Cytopathology; Data; Development; Disease; Dose; Drug Delivery Systems; Effectiveness; Enzymes; Family; Fibroblasts; Foundations; Frequencies; Galactosamine; Galactose; Gender; Genetic; Glycolipids; Glycoproteins; Glycosaminoglycans; Goals; Health system; Heart; Hereditary Disease; Histology; Human; Human Genetics; IGF Type 2 Receptor; Image Analysis; In Vitro; Injection of therapeutic agent; Intervention; Intravenous; Kidney; Kinetics; L-Iduronidase; Lead; Learning; Lectin; Liver; Longitudinal Studies; Lysosomes; Mammalian Cell; Measurable; Measures; Mediating; Memory; Modeling; Mucopolysaccharidosis I; Mucopolysaccharidosis I H; Mus; Neuraxis; Neurologic; Neurological outcome; Organ; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Pharmacodynamics; Phase; Phenotype; Plant Leaves; Plants; Production; Progressive Disease; Protocols documentation; Public Health; Recombinants; Recovery; Reproducibility; Research; Ricin; Safety; Small Business Innovation Research Grant; Solid; Specificity; Spleen; Splenomegaly; Syndrome; Technology; Therapeutic; Tissues; Treatment Efficacy; United States National Institutes of Health; Urine; Visceral; Weight; animal data; animal efficacy; base; behavioral deficiency; cell type; cohort; correctional system; cost; design; disease phenotype; dosage; drug efficacy; drug production; early experience; early onset; enzyme activity; enzyme replacement therapy; follow-up; immunogenicity; improved; in vivo; innovation; lot production; mouse model; novel therapeutics; patient population; phase 1 study; phase 2 study; pre-clinical; pre-clinical research; preclinical study; public health relevance; research and development; scale up; trafficking; transcytosis; uptake

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.

该项目的长期目标是为具有创新的国会议员I患者开发改进的ERT， 在整合的同时，可以增强难以治疗器官（例如大脑）的ERT递送和疾病纠正 基于植物的生物生产的安全性和成本优势。 MPS I综合征是由遗传引起的 溶酶体酶α-l-二核苷酶（IDUA）的缺陷。而目前的ERT药物选择I 有效地治疗许多内脏器官，在中央疾病的明显使人衰弱的表现 神经系统（CNS）仍有待解决。以前通过BioStratate进行的细胞研究表明 该讲座对哺乳动物细胞表面上常见的糖蛋白和糖脂具有很高的亲和力 可以介导有效的细胞摄取，转胞病和iDua递送到溶酶体。体外分析 MPS I患者的成纤维细胞接受了我们的IDUA骨蛋白融合（称为IDUAL）的患者 有效纠正细胞疾病表型。我们的I阶段对该项目的可行性动物研究 已经表明，iDual可以传递到MPS I小鼠模型动物的大脑中 纠正该疾病的细胞和行为表型并实现了里程碑 第一阶段研究的目标。此后续提案的具体目标是1）评估体内 药物剂量水平，频率和CNS药物输送和MPS I小鼠的效率读数，2） iDual产品规模扩大，稳定性和资格协议，以支持先进的临床前研究，并 3）建立严格的临床前动物数据评估效率，治疗开始时的年龄，免疫原性， 长期给药后的性别效应和行为纠正。 实现该项目的第一阶段目标，显示了体内细胞和行为动物的效率 IDUAL为我们的演讲载体ERT Fusion Fusic递送技术提供了关键的概念验证。 这一第二阶段更新项目的总体目标是完成下一阶段的药物生产 扩大且高度严格的动物研究将为后续临床前奠定坚实的基础 支持成功启动临床跟踪的IND应用所需的研究。 对我们成功的该项目的成功概念研究的促进将为潜在的扎实基础 该杠杆药物输送技术平台的应用到以前各种各样的其他 很难治疗疾病。