Substrate Optimization Therapy: A Novel Therapy for Mucopolysaccharidosis

描述（由申请人提供）： 本申请中提出的研究将测试通过称为底物优化疗法（SOT）的新型治疗方法治疗粘多糖样变性（MPS）的可行性。 MPS是由通常降解糖胺聚糖（GAG）的酶突变引起的溶酶体贮积病家族。 由于缺乏突变的酶，GAG积累到毒性水平，导致广泛的症状，包括严重的精神发育迟滞，心脏功能障碍和早期死亡。目前的治疗试图通过IV输注特定的重组酶来弥补缺陷，即酶替代疗法（ERT）。 患者，尤其是轻度受累的患者，确实从ERT中获益，但获益有限，主要是因为输注的酶在血流受限的组织（如关节（滑膜囊）、心脏瓣膜（软骨）和脑（血脑屏障））中的渗透性极低。 此外，许多患者迅速产生对ERT的阻断抗体应答，这种效应在受影响最严重的患者中最为明显。 底物优化疗法是一种新型疗法，因为它使用了有史以来第一种小分子GAG生物合成抑制剂来微妙地塑造患者体内GAG的精细结构组成，使GAG能够在致病酶缺乏的情况下被降解。 小分子方法是上级的，因为它可以穿透相关组织，包括中枢神经系统、心脏瓣膜、骨和关节，加上它避免了那些最需要治疗的患者中的抗体抑制问题。此外，由于潜在的生物学和疾病发病机制，该方法将用单一治疗剂治疗MPS I和MPS II。 通过本申请中提出的研究，我们将确定最佳小分子SOT药物，用于MPS II小鼠模型中的概念验证有效性研究。 公共卫生相关性： 相关性本提案的目的是测试一种新的治疗方法治疗粘多糖样沉积症II（MPS II）的可行性。 MPS II是一种罕见的遗传性疾病，目前仅通过每周静脉注射进行部分管理。 通过这项资助，我们的目标是确定化合物，这是开发第一种口服CNS渗透剂治疗这种毁灭性疾病的关键起点。

DESCRIPTION (provided by applicant): Project Summary The studies proposed in this application will test the feasibility of treating mucopolysaccharidosis (MPS) through a novel therapeutic approach called Substrate Optimization Therapy (SOT). MPS is a family of lysosomal storage diseases caused by mutations in the enzymes that normally degrade glycosaminoglycans (GAGs). Because of deficiencies in the mutated enzymes, GAGs build up to toxic levels causing a wide range of symptoms including severe mental retardation, cardiac dysfunction, and early death. Current therapies attempt to compensate for the deficiencies by IV infusion of specific recombinant enzymes, Enzyme Replacement Therapy (ERT). Patients, especially those only mildly affected, do receive some benefit from ERT, however the benefit is limited primary because of minimal penetration of infused enzymes in tissues with restricted blood flow such as joints (synovial capsule), heart valve (cartilage), and brain (blood brain barrier). Further, many patients rapidly develop blocking antibody responses to ERT, an effect that is most pronounced in those patients that are most severely affected. Substrate Optimization Therapy is novel because it uses the first ever small molecule GAG biosynthesis inhibitors to subtlety shape the fine structural composition of GAGs in patients, enabling the GAGs to be degraded despite the pathogenic enzyme deficiency. The small molecule approach is superior because it can penetrate the relevant tissues including the central nervous system, heart valve, bone, and joints plus it avoids issues of antibody inhibition in those patients most in need of treatment. Also, due to the underlying biology and disease pathogenesis, this approach will treat both MPS I and MPS II with a single therapeutic agent. Through the studies proposed in this application, we will identify the best small molecule SOT agents for a proof of concept efficacy study in the mouse model of MPS II. PUBLIC HEALTH RELEVANCE: Relevance The goal of this proposal is to test the feasibility of a novel therapeutic approach to treating mucopolysaccharidosis II (MPS II). MPS II is a rare genetic disease that is currently only partially managed through weekly intravenous injections. Through this grant we aim to identify compounds that are the crucial starting point for the development of the first orally available CNS penetrant therapy for this devastating disease.