Clinical trial NCT03576729: MRS to Determine Neuroinflammation and Oxidative Stress in MPS I
Official title: Magnetic Resonance Spectroscopy (MRS) to Determine Neuroinflammation and Oxidative Stress in MPS I
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Mucopolysaccharidosis Type I
Keywords: Mucopolysaccharidosis type I
MPS I
MPS IH
MPS IHS
MPS IS
Mucopolysaccharidosis I
Lead sponsor: University of Minnesota
Sponsor class: OTHER
Collaborators: name: Rare Diseases Clinical Research Network
name: National Center for Advancing Translational Sciences (NCATS)
name: National Institute of Neurological Disorders and Stroke (NINDS)
name: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
name: Lysosomal Disease Network
First posted: 2018-07-03
Enrollment: 30
Sex: ALL
Minimum age (years): 6
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: OTHER
Time perspective: PROSPECTIVE
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.

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Brain Magnetic Resonance Imaging/Magnetic Resonance Spectroscopy (MRI/MRS)
timeFrame: 1 day -Single encounter during an appointment which is set at time of study enrollment.
Secondary outcomes:
measure: Presence and Level of Neuroinflammatory Biomarker MIP-1alpha
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Regulated and Normal T cell Expressed and Secreted (RANTES)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Tumor Necrosis Factor Alpha (TNF-α)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Interferon-gamma (IFN-γ)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Interleukin 1 beta (IL1β)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Interleukin 2 (IL2)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Interleukin 8 (IL8)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Total Glutathione
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Determination of Blood Glutathione Redox Ratio
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Superoxide Dismutase (SOD)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of 8-isoprostane
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Levels of Thiobarbituric Acid Reactive Substances (TBARS)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of 4-hydroxynonenal (4-HNE)
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
measure: Presence and Level of Catalase
timeFrame: 1 day -Single blood draw performed at the same time as the single neuroimaging encounter.
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: University of Minnesota
name: Igor Nestrasil, PhD, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
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.