MRS to Determine Neuroinflammation and Oxidative Stress in MPS I

Study Overview
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Brief Summary
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Neuroinflammation and oxidative stress have been shown to be present in persons with mucopolysaccharidosis type I (MPS I), but their effect on disease severity and disease progression is unknown. The investigator intends to employ brain magnetic resonance spectroscopy (MRS), a non-invasive technique, along with analysis of neuroinflammation and oxidative stress biomarkers in the blood, to measure and determine the level of oxidative stress and neuroinflammation, and their impact on clinical variability in MPS I patients.

Detailed Description
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Persons with MPS I have a wide range of clinical manifestations including central nervous system (CNS) impairment. The role of neuroinflammation and oxidative stress is one avenue of investigation which may clarify the broad neurological impairment in MPS I. Finding biomarkers that accurately describe the underlying and ongoing brain pathology is a key not only to understanding the disease, but also to understanding the possibility of new therapeutic approaches for MPS I patients. The investigator will compare patients with Hurler syndrome, and Hurler-Scheie or Scheie syndrome, with healthy controls. There will be 10 participants in each group, resulting in a total of 30 participants. Within the Hurler-Scheie or Scheie syndrome group, the investigator will examine the association of clinical severity with the proposed measures. These findings might help determine whether hematopoietic cell transplantation (HCT), which is the treatment for Hurler syndrome patients, results in decreased oxidative stress and neuroinflammation as compared to Hurler-Scheie or Scheie syndrome patients, who are treated by enzyme replacement therapy (ERT). Additionally, these findings might help determine whether therapies directed at reducing neuroinflammation and oxidative stress in MPS I could enhance neurological outcomes. Study hypothesis: neuroinflammation and oxidative stress are present in MPS I subjects and are reflective of disease severity.

Official Title
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Magnetic Resonance Spectroscopy (MRS) to Determine Neuroinflammation and Oxidative Stress in MPS I

Conditions
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Mucopolysaccharidosis Type I

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: MPS I participants must meet the following: Diagnosis of Hurler syndrome, OR Hurler-Scheie syndrome, OR Scheie syndrome 6 years of age or older at time of screening Healthy control participants must meet all of the following: Absence of neurological disorder 6 years of age or older at time of screening Exclusion Criteria: Persons who have any of the following will not be enrolled in this study: Any surgically implanted pacemaker Any indwelling electronic device, including programmable shunts Orthodontic braces, unless non-metallic Other implanted metal in the body other than titanium An inability or unwillingness to complete an MRI/MRS because of low cognitive function or behavioral dysregulation Pregnancy

Ages Eligible for Study
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Minimum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Hurler syndrome participants<br>Participants who have MPS IH, also called Hurler syndrome | |
| Hurler-Scheie/Scheie participants<br>Participants who have either MPS IHS or MPS IS. MPS IHS is also called Hurler-Scheie syndrome. MPS IS is also called Scheie syndrome. | |
| Healthy Controls<br>Age-matched healthy controls | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brain Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy (MRI/MRS) | In a single session, each participant will undergo unsedated brain magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) to determine the presence and extent of any brain neuroinflammation. These data will be acquired on the 7-Tesla Siemens Prisma scanner at the Center for Magnetic Resonance Research (CMRR) at the University of Minnesota in Minneapolis. | 1 day -Single encounter during an appointment which is set at time of study enrollment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence and Level of Neuroinflammatory Biomarker MIP-1alpha | The presence of macrophage inflammatory protein (MIP)-1α (MIP-1alpha) will be determined; and if present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Regulated and Normal T cell Expressed and Secreted (RANTES) | The presence of 'regulated and normal T cell expressed and secreted' (referred to as RANTES), alternatively also known as chemokine (C-C motif) ligand 5, or CCL5, will be determined. If present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Tumor Necrosis Factor Alpha (TNF-α) | The presence of tumor necrosis factor alpha (TNF-α) will be determined. If present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Interferon-gamma (IFN-γ) | The presence of interferon-gamma (IFN-γ) will be determined. If present, the level of this autoinflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Interleukin 1 beta (IL1β) | The presence of interleukin 1 beta (IL1β) will be determined. If present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Interleukin 2 (IL2) | The presence of interleukin 2 (IL2) will be determined. If present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Interleukin 8 (IL8) | The presence of interleukin 8 (IL8), alternatively referred to as chemokine (C-X-C motif) ligand 8, or CXCL8, will be determined. If present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Total Glutathione | The presence of total glutathione will be determined. If present, the level of this antioxidant will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Determination of Blood Glutathione Redox Ratio | The blood glutathione redox ratio will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Superoxide Dismutase (SOD) | The presence of superoxide dismutase (SOD) will be determined. If present, the level of this antioxidant will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of 8-isoprostane | The presence of 8-isoprostane will be determined. If present, the level of this inflammatory biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Levels of Thiobarbituric Acid Reactive Substances (TBARS) | The presence of thiobarbituric acid reactive substances (TBARS), which are biomarkers of the damage produced by oxidative stress, will be determined. If present, the levels of these biomarkers will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of 4-hydroxynonenal (4-HNE) | The presence of 4-hydroxynonenal (4-HNE) will be determined. If present, the level of this oxidative stress biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 
| Presence and Level of Catalase | The presence of catalase will be determined. If present, the level of this oxidative stress biomarker will be determined. | 1 day -Single blood draw performed at the same time as the single neuroimaging encounter. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mucopolysaccharidosis type I, MPS I, MPS IH, MPS IHS, MPS IS, Mucopolysaccharidosis I