Biomarkers for Neurogenetic Disease Progression

MPS IIIB is a genetic disorder caused by mutations in the gene that encodes a-N-acetylglucosaminidase (NAGLU), an enzyme that is essential in the degradation of heparan sulfate glycosaminoglycans (HS-GAG). The primary pathology of MPS IIIB is the accumulation of HS-GAGs, leading to severe neurological manifestations, broad somatic disorders, and premature death. At the time of this publication, there were no effective biomarkers or treatments available for MPS IIIB. The researchers in the following study found that systemic delivery of the rAAV9-hNAGLU vector not only restored functional NAGLU and cleared lysosomal storage pathology in the central nervous system (CNS), but also corrected impaired neurodegenerative pathways in the brain and blood.¹

The Challenge: Finding Biomarkers for Mucopolysaccharidosis (MPS) IIIB

As of the writing of this article, there are no published biomarkers for MPS IIIB corresponding to neurological disease severity or therapeutic responsiveness. The lack of effective biomarkers for MPS IIIB poses challenges to the translation of gene therapy to the clinic. The data suggested that molecular changes in blood may reflect pathological status in the CNS and provide a useful tool for identifying biomarkers for MPS IIIB.

Metabolon Insight: Metabolomics Identifies Biomarkers for Mucopolysaccharidosis MPS IIIB

The metabolomics testing conducted by Metabolon helped identify metabolic biomarkers for MPS IIIB for the first time. Using the Metabolon Global Discovery Panel, blood serum samples were processed and analyzed from wild-type (WT), MPS IIIB, and MPS IIIB mice that were treated with an intravenous injection of rAAV9-hNAGLU.

The Solution: Metabolites Offer Great Surrogate Biomarker Potential for Mucopolysaccharidosis MPS IIIB

Global metabolomic profiling by mass spectrometry was performed on serum samples from MPS IIIB and WT mice to assess metabolic abnormalities related to MPS IIIB. The Metabolon Global Discovery Panel detected profound metabolic abnormalities in 231 metabolites of MPS IIIB mice. Significant decreases were observed in multiple serum metabolites that are critical for neurological function, neurotransmitter metabolism, energy production, and absorption and biosynthesis of amino acids. Sera from rAAV9-hNAGLU-treated MPS IIIB mice were also analyzed with the Metabolon Global Discovery Panel to evaluate their metabolic response to treatment. They showed that rAAV9-hNAGLU vector restored the metabolic profile of MPS IIIB mice, leading to a near-complete correction of all serum metabolite abnormalities (87% normalized, 13% over-corrected). Using an enzyme activity assay and a GAG quantification method, they demonstrated that the rAAV9-hNAGLU vector restored NAGLU activity and cleared HS-GAG storage in the brain and other soft tissues. This showed that the vector is functional and sufficient for the correction of lysosomal storage pathology in both the CNS and somatic tissues. Behavioral tests showed that rAAV9-hNAGLU also led to improvement in behavior performance, indicating a functional correction of MPS IIIB. Finally, rAAV9-hNAGLU-treated MPS IIIB mice exhibited extended survival. These data support the functional neurological benefits of rAAV9-hNAGLU gene delivery since premature death in MPS IIIB has been attributed to neurological disorders.

The Outcome: Serum-derived Metabolites Can Assess Neurological Disease Progression

As therapeutic development advances and more therapies for MPS become available, the lack of accessible biomarkers will be a critical challenge for therapeutic assessment. Translational research tools like the Metabolon Global Discovery Panel offer the ability to analyze the serum metabolomic profiles of other types of MPS or other neurological diseases. This will ultimately allow the identification of specific biomarkers (metabolites) for assessing disease progression, severity, and therapeutic outcome for these diseases. The researchers have elucidated a metabolomic fingerprint that will allow the assessment of disease progression, severity, and therapeutic outcome in an MPS IIIB mouse model. They showed that serum could be used to identify biomarkers (metabolites) of neurogenetic diseases like MPS IIIB. This also demonstrated that molecular changes in blood reflect changes in pathology status in the nervous system. “Utilizing metabolomics to further characterize the neurological disease MPS IIIB added invaluable insight into the systemic biology of the diseased mice. The researchers’ work demonstrates the viable use of gene therapies to treat human neurological disorders and the role metabolomics can play in characterizing these diseases, not only in mouse models, but human subjects as well,” says Katie Steward, Ph.D., Field Applications Scientist at Metabolon, Inc. In the future, this same approach could be used to examine the neurological disease status of a human subject from only blood serum.