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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
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Special Emphasis Panel (ZRG1-ETTN-C (11))
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Morris, Jill A
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Zacharon Pharmaceuticals, Inc.
San Diego
United States
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