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通过创新为MPS I患者开发改进的ERT