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（由适用提供）：该提案的目的是针对罕见的遗传疾病开发一种酶替代疗法（ERT）方法，该方法有效地减轻了阻碍先前ERT技术的免疫敏感性问题。对于那些可获得认可的重组酶产物的稀有遗传疾病，酶替代疗法仍然是最有效的治疗方法。 ERT对于治疗几种溶酶体疾病（LDS）至关重要，这些溶酶体疾病以其严重的形式出现受影响儿童的毁灭性多器官病理。然而，患者抗抗体抗体的诱导（免疫敏感性）已成为ERTS有效性的显着限制，从而改变了酶的分布和活性。由于早期/婴儿发作的形式是最严重的突变，因此在年轻患者中，免疫敏化的发展更为普遍。这些孩子经常在治疗时表现出巨大的挽救生命的改善。但是，随着这些患者形成对ERT药物的中和抗体，进度停止或迅速下降。当前批准的LDS批准的ERT剥削了相同的Mannose-6-Phoptate（M6P）受体，以吸收疾病细胞，而主要类别的抗ART抗体类别干扰了这种摄取过程。然而，生物制度开发的ERT技术LC开发的ERT-RTB融合机制用于细胞摄取，我们在使用Hurler MPS I溶酶体疾病细胞培养的初步实验中发现，活跃的ERT-RTB在含有免疫敏感动物的血清中和含有中和的抗体的情况下成功地传递了活性ERT-RTB。基于这些在体外结果的承诺，我们在SBIR第1阶段中的目标是证明体内效率，包括酶递送和ERT敏感的Hurler小鼠中的酶递送和葡糖胺聚糖（GAG）底物还原。我们先前证明IDUA：RTB显示出广泛的生物分布并纠正MPS I鼠标模型中的GAG底物水平。第一阶段的具体目的包括：1）开发对Rhidu ert产物免疫敏感的MPS I小鼠，以及2）比较RHIDU敏感小鼠中所选组织中的IDUA活性和GAG水平，遵循RHIDU或IDUA或IDUA：RTB。这些实验的成功将表明，在用IDUA-RTB经文治疗RHIDU后，ERT酶活性的显着增加将递送给IDUA敏感跨越小鼠的器官。基于一项成功的I期可行性研究，II期研究将针对MSP I动物模型中的统计学意义评估，以及RTB讲座平台应用于其他疾病，例如庞贝和其他疾病，这些疾病和其他疾病受到了免疫敏感性问题的影响最大，成功地影响了治疗。长期的目标是为患者开发新的免疫减轻ERT，这些ERT将为溶酶体和其他蛋白质缺乏疾病提供这些疗法的可持续效率。