Enzyme Replacement Therapeutics for Rare Childhood Genetic Diseases: An ERT Delivery System that Mitigates Immune-sensitization

罕见儿童遗传病的酶替代疗法：减轻免疫敏化的 ERT 递送系统

• 批准号: 9048190
• 负责人: Walter Acosta
• 金额: $ 22.5万
• 依托单位: BIOSTRATEGIES, LC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9048190
• 关键词: Address; Affect; Aftercare; Animal Model; Animals; Antibodies; Biodistribution; Biological Assay; Brain; Canis familiaris; Cell Culture Techniques; Cells; Child; Childhood; Collaborations; Deficiency Diseases; Development; Developmental Bone Diseases; Disease; Disease model; Dog Diseases; Drug Delivery Systems; Effectiveness; Enzymes; Family; Feasibility Studies; Fibroblasts; Gaucher Disease; Gifts; Glycogen storage disease type II; Goals; Healthcare Systems; Heart; Hereditary Disease; Human; Human Genetics; IGF Type 2 Receptor; Immune; Immune Sera; Immunization; Immunoglobulin G; In Vitro; Kidney; L-Iduronidase; Lectin; Life; Lysosomal Storage Diseases; Mammalian Cell; Mannose; Measures; Mediating; Modeling; Mucopolysaccharidosis I; Mucopolysaccharidosis VI; Mus; Mutation; Organ; Pathology; Patients; Pharmaceutical Preparations; Phase; Plants; Polysaccharides; Process; Production; Protein Deficiency; Public Health; Rattus; Recombinant Proteins; Recombinants; Reporting; Research; Route; Safety; Serum; Small Business Innovation Research Grant; System; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; United States National Institutes of Health; Urine; base; cell type; cost; effective therapy; enzyme activity; enzyme replacement therapy; glucosaminoglycans; immunogenicity; in vivo; infancy; innovation; mouse model; neutralizing antibody; novel therapeutics; patient population; pre-clinical; public health relevance; receptor; research study; response; success; therapeutic enzyme; trafficking; uptake

 DESCRIPTION (provided by applicant): The goal of this proposal is to develop an enzyme replacement therapy (ERT) approach for rare genetic diseases that is effective in mitigating the problem of immune sensitization that has hindered previous ERT technologies. Enzyme replacement therapies remain the most effective treatment for those rare genetic diseases for which approved recombinant enzyme products are available. ERTs have been crucial in treating several lysosomal diseases (LDs), which in their severe forms present with devastating multi-organ pathologies in affected children. However, the induction of patient anti-ERT antibodies (immune sensitization) has emerged as a significant limitation in the effectiveness of ERTs, altering enzyme distribution and activity. Because early/infantile-onset forms comprise the most severe mutations, the development of immune sensitization is much more prevalent in younger patients. These children often show dramatic life-saving improvements upon treatment onset. However, progress stops or quickly declines as these patients develop neutralizing antibodies to the ERT drug. Most currently approved ERTs for LDs exploit the same Mannose-6-Phospate (M6P) receptor for uptake into disease cells and the predominant class of anti-ERT antibodies interfere with this uptake process. However, the ERT technology developed by BioStrategies LC uses an alternative ERT-RTB fusion mechanism for cell uptake and we have found in preliminary experiments using Hurler MPS I lysosomal disease cell cultures that active ERT-RTB was successfully delivered in the presence of neutralizing antibody containing serum from immune-sensitized animals. Based on these promising in vitro results, our goal in this SBIR Phase 1 is to demonstrate in vivo efficacy, including enzyme delivery and glucosaminoglycan (GAG) substrate reduction, in ERT-sensitized Hurler mice. We previously demonstrated that IDUA: RTB shows broad bio-distribution and corrects GAG substrate levels in the MPS I mouse model. Specific aims for Phase I include to: 1) Develop MPS I mice that are immune sensitized to the rhIDU ERT product and 2) Compare IDUA activity and GAG levels in selected tissues in rhIDU-sensitized mice following treatments with either rhIDU or IDUA:RTB. Success of these experiments will demonstrate that a significant increase of ERT enzyme activity is delivered to organs of IDUA sensitized Hurler mice after treatment with IDUA-RTB verses rhIDU. Based on a successful Phase I feasibility study, Phase II research will target statistically significant assessments in the MSP I animal model and application of the RTB lectin platform to other diseases such as Pompe and other diseses where immune sensitization problems have most significantly impacted successful ERT treatments. The long-term goal is to develop new immune mitigating ERTs for patients that will provide sustainable efficacy of these therapies for lysosomal and other protein deficiency diseases.

 描述（由申请人提供）：该提案的目标是开发一种针对罕见遗传疾病的酶替代疗法（ERT）方法，该方法可有效缓解阻碍先前酶替代疗法技术的免疫敏化问题。对于那些已获得批准的重组酶产品的罕见遗传疾病的有效治疗对于治疗几种溶酶体疾病（LD）至关重要，这些疾病在严重时会导致毁灭性的多器官病变。然而，在受影响的儿童中，患者抗 ERT 抗体（免疫敏化）的诱导已成为 ERT 有效性的重大限制，因为早期/婴儿发病形式包含最严重的突变。免疫敏化的发生在年轻患者中更为普遍，这些儿童在治疗开始时通常表现出显着的挽救生命的改善，但是，随着这些患者对目前批准的 ERT 药物产生中和作用，进展会停止或迅速下降。 LD 利用相同的甘露糖 6-磷酸 (M6P) 受体摄取到疾病细胞中，并且主要类别的抗 ERT 抗体会干扰此摄取过程。然而，BioStrategies LC 开发的 ERT 技术使用替代的 ERT-RTB 融合机制。对于细胞摄取，我们在使用 Hurler MPS I 溶酶体疾病细胞培养物的初步实验中发现，在含有中和抗体的血清存在下，活性 ERT-RTB 能够成功传递基于这些有希望的体外结果，我们在 SBIR 第一阶段的目标是在 ERT 致敏的 Hurler 小鼠中证明体内功效，包括酶递送和葡糖胺聚糖 (GAG) 底物减少。 ：RTB 在 MPS I 小鼠模型中显示出广泛的生物分布并校正 GAG 底物水平，第一阶段的具体目标包括：1) 开发具有免疫能力的 MPS I 小鼠。 2) 比较 rhIDU 致敏小鼠在用 rhIDU 或 IDUA:RTB 治疗后选定组织中的 IDUA 活性和 GAG 水平。这些实验的成功将证明 ERT 酶活性显着增加。基于成功的 I 期可行性研究，II 期研究将针对 IDUA-RTB 与 rhIDU 治疗后的 IDUA 致敏 Hurler 小鼠的器官进行统计显着性评估。 MSP I 动物模型以及 RTB 凝集素平台在其他疾病（如庞贝氏症和其他免疫敏化问题对 ERT 治疗成功影响最大的疾病）中的应用长期目标是为患者开发新的免疫缓解 ERT，从而提供可持续的治疗。这些疗法对溶酶体和其他蛋白质缺乏疾病的疗效。