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

 描述（由申请方提供）：本提案的目标是开发一种用于罕见遗传性疾病的酶替代疗法（ERT）方法，该方法可有效缓解阻碍先前ERT技术的免疫致敏问题。酶替代疗法仍然是那些罕见的遗传性疾病的最有效的治疗方法，批准的重组酶产品是可用的。Erts在治疗几种溶酶体疾病（LD）方面至关重要，这些疾病的严重形式在受影响的儿童中表现为毁灭性的多器官病理学。然而，患者抗ERT抗体的诱导（免疫致敏）已成为Erts有效性的显著限制，改变了酶的分布和活性。由于早期/发作型包括最严重的突变，免疫致敏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挽救生命的改善。然而，随着这些患者产生对ERT药物的中和抗体，进展停止或迅速下降。 大多数目前批准用于LD的Erts利用相同的甘露糖-6-磷酸（M6 P）受体摄取到疾病细胞中，并且主要类别的抗ERT抗体干扰该摄取过程。然而，BioStrategies LC开发的ERT技术使用替代的ERT-RTB融合机制进行细胞摄取，并且我们在使用Hurler MPS I溶酶体病细胞培养物的初步实验中发现，在存在含有免疫致敏动物血清的中和抗体的情况下，成功递送了活性ERT-RTB。基于这些有希望的体外结果，我们在SBIR第1阶段的目标是在ERT致敏的Hurler小鼠中证明体内疗效，包括酶递送和葡糖胺聚糖（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校正GAG底物水平。I期的具体目标包括：1）开发对rhIDU ERT产品免疫致敏的MPS I小鼠，2）比较rhIDU或IDUA：RTB处理后rhIDU致敏小鼠选定组织中的IDUA活性和GAG水平。这些实验的成功将证明，与rhIDU相比，IDUA-RTB处理后，ERT酶活性显著增加至IDUA致敏Hurler小鼠的器官。 基于成功的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显著性评估以及RTB凝集素平台在其他疾病（如庞贝氏症和免疫致敏问题对成功的ERT治疗影响最大的其他疾病）中的应用。长期目标是为患者开发新的免疫缓解Erts，为溶酶体和其他蛋白质缺乏症提供可持续的疗效。

 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.