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

描述（由申请人提供）：本申请的目标是开发一种生物标志物，能够明确诊断和监测粘多糖病（MPS） I、II和VI患者的治疗反应。这些疾病是罕见的遗传疾病，每一种疾病都是由糖胺聚糖（GAGs）降解所需的溶酶体酶的独特缺陷引起的。由此产生的GAG片段的溶酶体积累导致严重的身体、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积累是由溶酶体酶缺乏引发的主要细胞事件，因此测量GAGs是该疾病的理想生物标志物。不幸的是，由于聚合物长度和磺化程度变化极大，以及生物样品中通常存在的非致病性GAG的重要背景，先前量化GAG积累的尝试一直没有成功。Sensi- Pro方法使用一种创新的方法来量化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疾病都缺乏一种独特的溶酶体降解酶，因此每种MPS疾病的sens - pro生物标志物是离散的，在未受影响的人群中没有发现。除了能够监测个体患者对FDA批准的疗法的反应外，sensipro检测还证明了快速准确区分各种MPS疾病的能力。该提案旨在进一步开发sens - pro检测方法，用于临床鉴别诊断和测量MPS I、II和VI的治疗反应。这将通过与ARUP实验室合作的一系列研究来完成，这些研究旨在建立MPS I、II和VI生物标志物的标准，多重检测，并在符合CLIA的环境中验证检测方法。随着多重检测方法的建立，它将被测试区分MPS疾病的能力，并检测来自MPS i临床试验样品的治疗反应。一旦成功完成，该检测方法将由ARUP实验室商业化，作为MPS患者的最终鉴定和治疗方案优化的临床检测方法。

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.