Substrate Optimization Therapy: A Novel Therapy for Mucopolysaccharidosis

描述(由申请人提供)： 项目概述本申请中提出的研究旨在将治疗粘多糖病(MPS)的创新方法推向临床试验。MPS是一种溶酶体储存疾病家族，由通常降解糖胺多聚糖(GAG)的酶突变引起。由于突变酶的缺乏，GAG会积累到有毒的水平，导致一系列症状，包括严重的智力低下、心脏功能障碍和过早死亡。目前的治疗方法试图通过静脉输注特定的重组酶来弥补这些不足，即酶替代疗法(ERT)。患者，特别是那些仅受轻微影响的患者，确实从ERT中获得了一些好处，但这种好处是有限的，因为注入的酶在血液流动受限的组织中渗透很少，如关节(滑膜)、心脏瓣膜(软骨)和脑(血脑屏障)。此外，许多患者对ERT迅速产生阻断抗体反应，这种影响在受影响最严重的患者中最为明显。我们的治疗方法(底物优化治疗，SOT)是新颖的，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。小分子方法更优越，因为它可以穿透相关组织，包括中枢神经系统、心脏瓣膜、骨骼和关节，而且它避免了那些最需要治疗的患者的抗体抑制问题。此外，由于潜在的生物学和疾病发病机制，该方法将使用单一治疗剂治疗MPS I、II和III。通过本申请中建议的研究，我们将完成启动I期临床试验所需的临床前研究和IND启用研究。 公共卫生相关性： 本提案的目标是开发一种治疗粘多糖病(MPS)的新疗法。MPS是一组罕见的儿童遗传性疾病，目前只能通过每周静脉注射进行部分治疗，这些注射不能治疗由这些疾病引起的神经缺陷。通过这笔赠款，我们的目标是开发第一种疗法来治疗所有症状，包括这些疾病的破坏性神经缺陷。

DESCRIPTION (provided by applicant): Project Summary The studies proposed in this application are aimed at progressing an innovative approach to treating mucopolysaccharidoses (MPS) toward clinical trials. 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. Our therapeutic approach (Substrate Optimization Therapy, SOT) 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 MPS I, II, and III with a single therapeutic agent. Through the studies proposed in this application, we will complete the preclinical and IND enabling studies required to initiate a Phase I clinical trial. PUBLIC HEALTH RELEVANCE: Relevance The goal of this proposal is to develop a new therapy for treating mucopolysaccharidosis (MPS). MPS is a collection of rare childhood genetic diseases that are currently only partially managed through weekly intravenous injections that do not treat the neurological deficits arising from the diseases. Through this grant we aim to develop the first therapy to treat all symptoms including the devastating neurological deficits of these diseases.