MRS to Determine Neuroinflammation and Oxidative Stress in MPS I

October 30, 2019 updated by: University of Minnesota

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

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.

Study Overview

Status

Completed

Conditions

Detailed Description

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.

Study Type

Observational

Enrollment (Actual)

30

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Minnesota
      • Minneapolis, Minnesota, United States, 55455
        • University of Minnesota

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

6 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

20 subjects who have MPS I and are 6 years of age or older will be recruited for this study: 10 with severe MPS I (post-HCT Hurler syndrome); and 10 with attenuated MPS I (Hurler Scheie or Scheie syndrome, and receiving ERT).

In addition, 10 normal healthy controls, 6 years of age or older, will be recruited for this study.

Description

Inclusion Criteria:

MPS I participants must meet the following:

  1. Diagnosis of Hurler syndrome, OR Hurler-Scheie syndrome, OR Scheie syndrome
  2. 6 years of age or older at time of screening

Healthy control participants must meet all of the following:

  1. Absence of neurological disorder
  2. 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:

  1. Any surgically implanted pacemaker
  2. Any indwelling electronic device, including programmable shunts
  3. Orthodontic braces, unless non-metallic
  4. Other implanted metal in the body other than titanium
  5. An inability or unwillingness to complete an MRI/MRS because of low cognitive function or behavioral dysregulation
  6. Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Hurler syndrome participants
Participants who have MPS IH, also called Hurler syndrome
Hurler-Scheie/Scheie participants
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
Age-matched healthy controls

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Brain Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy (MRI/MRS)
Time Frame: 1 day -Single encounter during an appointment which is set at time of study enrollment.
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
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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)
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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
Time Frame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
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.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Minnesota

Collaborators

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
National Institute of Neurological Disorders and Stroke (NINDS)
Rare Diseases Clinical Research Network
National Center for Advancing Translational Sciences (NCATS)
Lysosomal Disease Network

Investigators

  • Principal Investigator: Igor Nestrasil, PhD, MD, University of Minnesota

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 1, 2018

Primary Completion (Actual)

August 31, 2019

Study Completion (Actual)

August 31, 2019

Study Registration Dates

First Submitted

June 22, 2018

First Submitted That Met QC Criteria

July 2, 2018

First Posted (Actual)

July 3, 2018

Study Record Updates

Last Update Posted (Actual)

November 1, 2019

Last Update Submitted That Met QC Criteria

October 30, 2019

Last Verified

October 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • STUDY00003680
  • U54NS065768 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

De-identified individual data is input to the NIH-funded Rare Diseases Clinical Research Network's Data Management & Coordinating Center ("DMCC"). Eventually this data will become part of the database of Genotypes and Phenotypes ("dbGaP"), which is part of the National Center for Biotechnology Information, U.S. National Library of Medicine.

IPD Sharing Time Frame

De-identified individual data are input to the NIH-funded Rare Diseases Clinical Research Network's Data Management & Coordinating Center ("DMCC") as these data become available following participants' appointments. After the conclusion of this study and analysis of its data, these data will become part of the database of Genotypes and Phenotypes ("dbGaP"), which is part of the National Center for Biotechnology Information, U.S. National Library of Medicine. These data will remain available in this database indefinitely.

IPD Sharing Access Criteria

Access criteria are determined by the National Center for Biotechnology Information, U.S. National Library of Medicine.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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