MRS to Determine Neuroinflammation and Oxidative Stress in MPS I

Mucopolysaccharidosis Type I Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03576729
• Other study ID #: STUDY00003680
• Secondary ID: U54NS065768
• Status: Completed
• Start date: November 1, 2018
• Est. completion date: August 31, 2019

Study information

• Verified date: October 2019
• Source: University of Minnesota
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: August 31, 2019
• Est. primary completion date: August 31, 2019
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 6 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Mucopolysaccharidoses
• Mucopolysaccharidosis I
• Mucopolysaccharidosis Type I

Locations

Country	Name	City	State
United States	University of Minnesota	Minneapolis	Minnesota

Sponsors (6)

Lead Sponsor	Collaborator
University of Minnesota	Lysosomal Disease Network, National Center for Advancing Translational Science (NCATS), National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS), Rare Diseases Clinical Research Network

Country where clinical trial is conducted

United States, 

References & Publications (2)

Nestrasil I, Vedolin L. Quantitative neuroimaging in mucopolysaccharidoses clinical trials. Mol Genet Metab. 2017 Dec;122S:17-24. doi: 10.1016/j.ymgme.2017.09.006. Epub 2017 Sep 15. Review. — View Citation

Shapiro EG, Nestrasil I, Rudser K, Delaney K, Kovac V, Ahmed A, Yund B, Orchard PJ, Eisengart J, Niklason GR, Raiman J, Mamak E, Cowan MJ, Bailey-Olson M, Harmatz P, Shankar SP, Cagle S, Ali N, Steiner RD, Wozniak J, Lim KO, Whitley CB. Neurocognition across the spectrum of mucopolysaccharidosis type I: Age, severity, and treatment. Mol Genet Metab. 2015 Sep-Oct;116(1-2):61-8. doi: 10.1016/j.ymgme.2015.06.002. Epub 2015 Jun 17. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Presence and Level of Neuroinflammatory Biomarker MIP-1alpha	The presence of macrophage inflammatory protein (MIP)-1a (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.
Secondary	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.
Secondary	Presence and Level of Tumor Necrosis Factor Alpha (TNF-a)	The presence of tumor necrosis factor alpha (TNF-a) 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.
Secondary	Presence and Level of Interferon-gamma (IFN-?)	The presence of interferon-gamma (IFN-?) 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.
Secondary	Presence and Level of Interleukin 1 beta (IL1ß)	The presence of interleukin 1 beta (IL1ß) 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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.
Secondary	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.

External Links

•   Lysosomal Disease Network's web site
•   Rare Diseases Clinical Research Network's web site