Clinical trial NCT04257513: Clinical Study to Monitor Plasma Levels of 24OHC in Subject with HD
Official title: Innovative Therapeutic Strategy Targeting Neurons with Cholesterol in Huntington Disease: from Preclinical Studies to Clinical Trial Readiness
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Huntington Disease
Keywords: Huntington Disease
Cholesterol
Lead sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
Sponsor class: OTHER
Collaborators: name: Istituto Di Ricerche Farmacologiche Mario Negri
First posted: 2020-02-06
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: At least 60 subjects (both males and females) will be enrolled in the study. Eligible participants include healthy controls, people who are in the presymptomatic stage of HD, and people with symptomatic HD at different disease stage (I-III).

Brief summary: A 2-year clinical longitudinal study to measure plasma concentrations of 24S-hydroxycholesterol, a brain-derived cholesterol catabolite, in subjects with Huntington disease, from the presymptomatic to the symptomatic stages.

Detailed description: In cross-sectional studies, the plasma level of brain-derived 24S-hydroxycholesterol (24OHC) has been found to be significantly diminished in HD patients from the first stages of the disease. Furthermore, in HD gene-positive pre-symptomatic (pre-HD) the plasma levels can predict the development of motor signs of disease in subjects closer to onset, better than in subjects far from onset. These data suggest that circulating 24OHC might be a candidate biomarker for phenotypic conversion and for disease progression in different stages of the disease.

Detailed neurological, cognitive and imaging data and blood samples will be collected at baseline, and after two years to investigate the rate of changes along the longitudinal study. Isotope dilution mass spectrometry (assay performed at Istituto di Ricerche Farmacologiche Mario Negri IRCCS) will be used to measure the plasma levels of brain-derived 24OHC and other sterols reflecting peripheral cholesterol synthesis. The investigators expect to establish whether changes in plasma 24OHC mark disease progression and, eventually, phenoconversion from pre-symptomatic to symptomatic stages in combination with clinical, cognitive and imaging parameters.

Eligibility criteria: Inclusion Criteria:

Symptomatic HD subjects

1. Age ≥ 18 years
2. Known family history of HD and genetically confirmed disease by direct DNA test (CAG expansion \> 35 repeats)
3. Clinical diagnostic motor features of HD, defined as score\> 5 at the motor Unified Huntington Disease Rating Scale (mUHDRS)
4. Stage I or II or III HD, defined as UHDRS Total Functional Capacity (TFC) scores between 3 and 13 inclusive (Marder, 2000)

Presymptomatic HD subjects

1. Age ≥ 18 years
2. Known family history of HD and genetically confirmed mutation by direct DNA test (CAG expansion \> 35 repeats)
3. Absence of clinical motor features of HD, defined as mUHDRS rating scale ≤ 5

Healthy Subjects

1. Age ≥ 18 years
2. Absence of known family history of HD or genetically confirmed negative DNA test for HD (CAG expansion ≤ 35 repeats)
3. Absence of clinical motor features of HD, defined as mUHDRS rating scale ≤ 5

Exclusion Criteria:

1. Participation in clinical pharmacological trials
2. Inability to undergo and tolerate MRI scans (e.g. claustrophobia, severe chorea, MRI-incompatible intrauterine devices, metal implants, ect)
3. Inability or unwillingness to undertake any of the study procedures

Primary outcomes:
measure: plasmatic 24OHC levels
timeFrame: at baseline and after 2-years follow up visit
Secondary outcomes:
measure: Changes in the score of the Unified Huntington Disease Rating Scale (UHDRS)
timeFrame: after 2-years follow up visit
measure: Changes in score at the Digit Symbol Modalities Test (DSMT)
timeFrame: after 2-years follow up visit
measure: Changes in caudate nucleus volume measured at MRI
timeFrame: after 2-years follow up visit
Other outcomes:
Locations:
city: Milano
country: Italy
facility: UOC Genetica Medica e Neurogenetica
Study officials:
References: