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(申请人提供)：这项提案的目标是开发一种针对罕见遗传病的酶替代疗法(ERT)方法，该方法有效地缓解了阻碍先前ERT技术的免疫致敏问题。对于那些获得批准的重组酶产品的罕见遗传病，酶替代疗法仍然是最有效的治疗方法。ERT在治疗几种溶酶体疾病(LDS)方面至关重要，这些疾病的严重形式在受影响的儿童中呈现毁灭性的多器官病理。然而，患者抗ERT抗体的诱导(免疫致敏)已成为ERTS有效性的一个显著限制，改变了酶的分布和活性。由于早发/婴儿发病的形式包含最严重的突变，因此免疫敏感化的发展在年轻患者中更为普遍。这些儿童在治疗开始时往往表现出戏剧性的救命改善。然而，随着这些患者对ERT药物产生中和抗体，进展停止或迅速下降。目前大多数被批准用于LDS的ERT利用相同的甘露糖-6-磷酸(M6P)受体摄取到疾病细胞中，而主要类别的抗ERT抗体干扰这一摄取过程。然而，BioStrategy LC开发的ERT技术使用了另一种ERT-RTB融合机制来摄取细胞，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，在含有免疫致敏动物血清的中和抗体存在的情况下，成功地传递了活性ERT-RTB。基于这些有希望的体外结果，我们在SBIR第一阶段的目标是证明ERT致敏的Hurler小鼠的体内疗效，包括酶传递和氨基葡萄糖(GAG)底物减少。我们先前证明IDUA：rtb在MPS I小鼠模型中显示出广泛的生物分布，并纠正了GAG底物水平。第一阶段的具体目标包括：1)建立对rhIDU ERT产品免疫致敏的MPS I小鼠，以及2)比较经rhIDU或IDUA：RTB治疗后，受rhIDU致敏的小鼠选定组织中的IDUA活性和GAG水平。这些实验的成功将证明IDUA-RTB与rhIDU相比，IDUA-RTB治疗后ERT酶活性显著增加到IDUA致敏的Hurler小鼠的器官中。在成功的第一阶段可行性研究的基础上，第二阶段的研究将以MSP I动物模型中具有统计学意义的评估为目标，并将RTB凝集素平台应用于其他疾病，如Pompe和其他疾病，这些疾病的免疫敏化问题对成功的ERT治疗产生了最大的影响。长期目标是为患者开发新的免疫缓解ERT，为溶酶体和其他蛋白质缺乏性疾病提供这些疗法的持续疗效。