Development of a Novel Biomarker for Mucopolysaccharidosis I, II, and VI

描述（由申请方提供）：本提案的目的是开发一种生物标志物，能够明确诊断和监测粘多糖样变性（MPS）I、II和VI患者的治疗反应。这些疾病是罕见的遗传性疾病，每种疾病都是由降解糖胺聚糖（GAG）所需的溶酶体酶的独特缺陷引起的。由此产生的GAG片段的溶酶体蓄积导致严重的身体、发育和神经症状，不同患者之间具有显著的异质性。由于溶酶体GAG蓄积是由溶酶体酶缺乏引发的主要细胞事件，因此GAG的测量是该疾病的理想生物标志物。不幸的是，由于聚合物长度和硫酸化的极端可变性以及来自通常存在于生物样品中的非致病性GAG的显著背景，先前定量GAG积累的尝试一直不成功。Sensi-Pro方法使用一种创新的方法来定量由于特定溶酶体缺陷而产生的独特GAG结构，从而解决了这一问题。由于每种MPS疾病都缺乏不同的溶酶体降解酶，因此Sensi-Pro生物标志物对于每种MPS疾病是离散的，并且在未受影响的人中未发现。除了监测个体患者对FDA批准的治疗的反应的能力外，Sensi-Pro测定还证明了快速准确区分各种MPS疾病的能力。本提案旨在进一步开发Sensi-Pro检测试剂盒，用于MPS I、II和VI的鉴别诊断和治疗反应测量的临床应用。这将通过与ARUP实验室合作进行的一系列研究来实现，这些研究旨在建立MPS I、II和VI生物标志物的标准品，多重检测，并在符合CLIA的环境中验证检测。在建立多重检测试剂盒后，将检测其区分MPS疾病和检测MPS I临床试验样本中治疗应答的能力。成功完成后，该检测试剂盒将由ARUP实验室作为临床检测试剂盒进行商业化，用于确定MPS患者和优化治疗方案。 公共卫生相关性：本研究旨在开发一种新的生物标志物，用于粘多糖沉积症I、II和VI患者的明确诊断和临床管理。这些疾病是由降解碳水化合物所需的细胞系统缺陷引起的罕见遗传疾病。这项研究的成功结论将提供一个关键的诊断工具，使受影响的患者的识别，选择适当的 治疗和优化治疗策略。

DESCRIPTION (provided by applicant): The goal of this proposal is to develop a biomarker capable of definitively diagnosing and monitoring response to therapy in patients with Mucopolysaccharidosis (MPS) I, II and VI. These diseases are rare genetic conditions each caused by unique deficiencies in the lysosomal enzymes required for the degradation of glycosaminoglycans (GAGs). The resulting lysosomal accumulation of GAG fragments leads to severe physical, developmental, and neurological symptoms with dramatic heterogeneity between different patients. Since lysosomal GAG accumulation is the primary cellular event triggered by the lysosomal enzyme deficiency, the measurement of GAGs is an ideal biomarker of the disease. Unfortunately, prior attempts to quantify GAG accumulation have been unsuccessful due to the extremely variable polymer length and sulfation and significant background from non-pathogenic GAGs that are normally present in biological samples. The Sensi- Pro method solves this problem using an innovative approach to quantify the unique GAG structures that arise due to the specific lysosomal defect. Because each MPS disorder is deficient in a distinct lysosomal degradative enzyme, the Sensi-Pro biomarkers are discrete for each MPS disorder and are not found in unaffected people. The Sensi-Pro assay has demonstrated the ability to quickly and accurately differentiate the various MPS disorders in addition to the ability to monitor individual patient responses to the FDA approved therapies. This proposal aims to develop the Sensi-Pro assay further for clinical use for the differential diagnosis and measurement of response to therapy in MPS I, II and VI. This will be accomplished through a series of studies in collaboration with ARUP Laboratories designed to establish the standards for the MPS I, II, and VI biomarkers, multiplex the assay, and validate the assay in a CLIA compliant environment. With the multiplexed assay established, it will be tested for the ability to differentiate between MPS disorders and detect a response to therapy in samples from a clinical trial for MPS I. Upon successful completion, the assay will be commercialized by ARUP Laboratories as a clinical assay for the definitive identification of MPS patients and optimization of treatment protocols. PUBLIC HEALTH RELEVANCE: This research is designed to develop a novel biomarker for the definitive diagnosis and clinical management of patients with Mucopolysaccharidosis I, II, and VI. These diseases are rare genetic conditions caused by defects in the cellular systems required to degrade carbohydrates. The successful conclusion of this research will provide a critical diagnostic tool enabling the identification of affected patients, selection of appropriate therapy, and optimization of treatment strategies.