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

描述(由申请人提供)：这项提案的目标是开发一种生物标记物，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，每种疾病都是由降解糖胺多聚糖(GAG)所需的溶酶体酶的独特缺陷引起的。由此产生的GAG片段的溶酶体积聚导致严重的身体、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积聚是溶酶体酶缺乏引发的主要细胞事件，因此GAG的测定是一种理想的疾病生物标志物。不幸的是，由于生物样品中通常存在的非致病性GAG的高度可变的聚合物长度和硫酸盐化以及重要的背景，先前对GAG累积进行量化的尝试一直没有成功。Sensi-Pro方法解决了这个问题，它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的GAG结构。由于每种MPS疾病都缺乏一种独特的溶酶体降解酶，因此Sensi-Pro生物标记物对每种MPS疾病都是离散的，在未受影响的人中没有发现。Sensi-Pro检测已经证明，除了能够监测个体患者对FDA批准的治疗的反应外，还能够快速准确地区分各种MPS疾病。这项建议旨在进一步开发SENSI-Pro检测方法，用于MPS I、II和VI的临床鉴别诊断和治疗反应测量。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生物标记物的标准，多重检测，并在符合CLIA的环境中验证检测。随着多重测试的建立，它将在MPS I临床试验的样本中测试区分MPS疾病和检测治疗反应的能力。在成功完成后，ARUP实验室将把该测试作为MPS患者最终鉴定和治疗方案优化的临床测试进行商业化。 公共卫生相关性：这项研究旨在开发一种新的生物标记物，用于确定诊断和临床治疗粘多糖病I、II和VI患者。这些疾病是罕见的遗传疾病，由降解碳水化合物所需的细胞系统缺陷引起。这项研究的成功结束将提供一个关键的诊断工具，使之能够识别受影响的患者，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.